ABCMdb

ABCA4 p.Leu541Pro

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Publications

PMID: 21567408 [PubMed] Nakagawa H et al: "Ubiquitin-mediated proteasomal degradation of ABC transporters: a new aspect of genetic polymorphisms and clinical impacts."

No. Sentence Comment

155 Effect of Mutations and Nonsynonymous SNPs on Protein Trafficking, Maturation, or ERAD of ABC Transporters Protein AA Mutation/SNP Effect on Protein Reference ABCA1 W590S Mutation Functional defect 115 R587W Mutation Impaired glycol processing 115 Q597R Mutation Impaired glycol processing, ERAD 115,116 Y1532C Mutation Altered protein trafficking 117 R1925Q Mutation Altered protein trafficking 118 ABCA3 R43L Mutation Altered protein trafficking 119 L101P Mutation Altered protein trafficking 119 R280C Mutation Altered protein trafficking 119 ABCA4 L541P Mutation Mislocalization 120 R602W Mutation Mislocalization 120 A1038V Mutation Mislocalization 120 C1490Y Mutation Mislocalization 120 ABCB1a G268V Mutation ERAD 121 G341C Mutation ERAD 121 I1196S Mutation Reduced glycosylation 122 ABCB4 I541F Mutation Accumulation in ER 123 ABCB11a E135K Mutation Reduced level of mature protein 124 L198P Mutation Reduced level of mature protein 124 E297G Mutation Reduced level of mature protein 124 L413W Mutation Reduced level of mature protein 124 R432T Mutation Reduced level of mature protein 124 D482G Mutation Immature protein in ER 124,125 N490D Mutation Reduced level of mature protein 124 A570T Mutation Reduced level of mature protein 124 T655I Mutation Reduced level of mature protein 124 Y818F SNP Moderate reduction of protein 124 G982R Mutation Retention in ER 125 R1153C Mutation ERAD 125 R1286Q Mutation Retention in ER 125 ABCC2a R768W Mutation Impaired protein trafficking 126 I1173F Mutation Impaired protein maturation 127 R1392 Mutation Impaired protein maturation 128 M1393 Mutation Impaired protein maturation 129 ABCC4a E757K SNP Altered protein trafficking 23 ABCC7 F508 Mutation Misfolding, ERAD 36-39,130 G85E Mutation Impaired protein maturation 130-132 G91R Mutation Impaired protein maturation 130-132 N1303K Mutation Impaired protein maturation 130-132 ABCC8 WT Wild type Ubiquitin-proteasome degradation 133 A116P Mutation Ubiquitin-proteasome degradation 133 V187D Mutation Ubiquitin-proteasome degradation 133 F1388 Mutation Impaired protein trafficking 134 L1544P Mutation Impaired protein trafficking 135,136 ABCC11a G180R SNP Ubiquitin-proteasome degradation 50 27 Mutation Ubiquitin-proteasome degradation 50 ABCG2a V12M SNP Altered protein localization 96 Q141K SNP Ubiquitin-proteasome degradation 102 F208S SNP Ubiquitin-proteasome degradation 78,99 S441N SNP Ubiquitin-proteasome degradation 78,99 Mutations of ABCA1, ABCA3, ABCA4, ABCB4, ABCB11, ABCC2, ABCC7 (CFTR), and ABCC8 are associated with Tangier disease, fatal surfactant deficiency, Stargardt disease, progressive familial intrahepatic cholestasis type 3 (PFIC-3), progressive familial intrahepatic cholestasis type 2 (PFIC-2), Dubin-Johnson syndrome, cystic fibrosis, and familial hyperinsulinism, respectively. Login to comment

PMID: 9781034 [PubMed] Rozet JM et al: "Spectrum of ABCR gene mutations in autosomal recessive macular dystrophies."

No. Sentence Comment

44 Interestingly, the A1038V mutation was found in compound heterozygotes (one STGD, family CHE and one FFM, family VIL), the second mutation being another missense mutation in the FFM family (L541P) but a frameshift mutation in STGD (Table 1). Login to comment
45 Furthermore, all ABCR missense mutations Table 1 Mutations in the ABCR gene in STGD and FFM families Conserved aa in: Nucleotide change Amino acid change Domain ABCs RmP Phenotype Families Comment (571-2)A®G splicing mutation STGD 1 HAD1 (1938-2)A®G splicing mutation STGD 1 (4668+2)T®C splicing mutation STGD 1 (4735+2)T®A splicing mutation STGD 1 del(5196+1-5196+6 splicing mutation STGD 1 LOZ2 2570 delT frameshift mutation STGD 1 3209insGT frameshift mutation STGD 2 CHE2 G3754T E1252X STGD 1 C3994T Q1332X STGD 1 C6337G I2113X STGD 1 JEG2 C52T R18W IC - + STGD 1 C634T R212C EC - + STGD 5 GEN2, JEG2 G1908T Q636H IC - + STGD 1 LOZ2 C3056T T1019M IC - + STGD 1 C3322T R1107C IC - + STGD 1 JUL2 C4916T R1640W IC + + STGD 2 MAR1 G5929A G1977S ATP2 + + STGD 1 GEN2 G6320A R2107H IC + + STGD 1 JUL2 C3114T A1038V IC - + STGD 2 CHE2 +FFM +1 VII2 T1622C L541P EC - + FFM 1 VII2 T31C L11P IC + + FFM 1 G3272A G1090E IC + + FFM 1 G4522T G1508C IC + + FFM 1 C5908T L1970F IC + + FFM 1 GON2 T5912G L1971R IC + + FFM 1 GON2 Mutations refer to the standard nomenclature. Login to comment

PMID: 22661472 [PubMed] Testa F et al: "Correlation between photoreceptor layer integrity and visual function in patients with Stargardt disease: implications for gene therapy."

No. Sentence Comment

66 Clinical and Molecular Data of STGD Patients Patient ID/Fam Age (y) Visual Acuity OCT ft (lm) MP (dB) IS/OS* Fundus† FAF‡ ERG§ mfERGjj Mutation 1 Mutation 2 4/2 50 0.0715 134 5.25 - 1 - 2 4 G1961E 250InsCAAA 5/2 47 0.1 127 14.2 2 1 1 1 3 G1961E 250InsCAAA 6/3 33 0.05 125 9.8 2 2 2 1 3 G1961E R2149X 7/4 18 0.085 135 0 - 2 - 3 4 5917del G 5917del G 8/5 16 0.095 104 0.9 3 2 3 3 4 L541P; A1038V L541P; A1038V 9/6 71 0.03 109 0 3 3 3 2 4 IVS35þ2t > c G1961E 11/7 46 0.2 137 9.35 2 1 2 1 1 Y850K A1598D 13/8 35 0.017 163 0 - 3 - 3 4 L541P R1098C 15/10 20 0.1 135.5 11.05 2 1 1 1 4 IVS35þ2t > c G1961E 16/11 20 0.47 96 16.7 2 1 2 1 2 L541P; A1038V L541P; A1038V 17/11 34 0.1 114.5 7.55 2 1 2 1 3 L541P; A1038V L541P; A1038V 18/11 18 1 134 16.15 1 1 1 1 3 L541P; A1038V L541P; A1038V 19/12 12 0.12 242 6.5 3 1 2 1 2 L541P; A1038V L541P; A1038V 20/13 28 0.1 111 14.2 2 2 2 1 3 R1443H IVS35þ2t > c 21/14 34 0.2 152 14.15 2 1 2 2 4 R653C G1961E 22/15 69 0.079 122 0 3 3 3 3 4 I1562T R2149X 23/15 46 0.55 162 1.05 3 3 3 3 4 I1562T IVS45þ1g > c 25/16 28 0.11 105.5 3.1 3 2 2 3 4 R212C R212C 26/17 13 0.084 138.5 0.2 3 2 3 1 3 R18W C1490Y 27/4 20 0.0775 131 0 - 3 - 3 4 5917del G 5917del G 28/4 23 0.042 159.5 0 - 3 - 3 4 5917del G 5917del G 30/18 29 0.0375 103 0 3 3 3 3 4 N965S G1961E 31/19 17 0.1 102 9 3 2 2 3 4 L541P F655C 38/20 20 0.225 95 16 2 1 1 3 4 L541P G1961E 39/21 20 0.17 146 16.7 2 1 1 1 3 G1961E R2030X 42/22 43 0.575 127 7.05 2 1 2 1 2 250insCAAA G1961E 43/23 12 0.1 117.5 11.55 2 2 2 1 3 IVS40þ5g > a IVS15-8g > a 44/24 29 0.1 149 18.5 2 1 2 1 3 G1961E 4736del6bpins2bp 46/25 38 0.0075 182.5 0 - 3 - 3 4 G618R G1972R 48/26 35 0.46 133.5 12.25 2 1 - 1 3 4538insC G1961E 50/27 13 0.2 122.5 17.35 2 1 2 1 3 IVS35þ2t > c G1961E 51/28 24 0.065 123 0 3 3 3 3 4 250InsCAAA V767D 52/29 14 1 147 6.15 1 1 1 3 4 L2027F A1881V 53/30 45 0.1 120 6.05 3 2 2 1 3 G1961E R2030X 54/30 24 0.09 159 2.65 3 3 3 3 4 V767D R2030X 55/31 34 0.085 150 5.15 3 3 3 3 4 N96H IVS40þ5g > a 56/32 48 0.0335 118.5 4.4 - 3 - 2 4 IVS35þ2t > c G1961E 58/32 52 0.05 124 5.8 3 2 2 2 4 IVS35þ2t > c G1961E 60/33 43 0.065 163 15.95 2 1 - 1 2 250InsCAAA G1961E 61/34 45 0.03 187.5 4.5 1 1 1 2 1 R1640Q G1961E 64/35 33 0.0665 158 0 3 3 3 3 4 C2150R 2626InsTTT 65/35 38 0.008 172 0.05 3 3 3 3 4 C2150R 2626InsTTT 66/36 42 0.4 137 0.95 3 2 2 1 3 N96D IVS40þ5g > a 67/37 14 0.235 132 0.15 3 2 3 3 4 IVS6-2a > t IVS6-2a > t 69/38 19 0.09 120 0 3 1 2 1 3 R511H N529S 70/39 42 0.515 140 0.4 3 3 3 3 4 IVS40þ5g > a N965S 72/40 33 0.096 116.5 5.1 3 2 2 1 3 N96D L2140Q 73/41 17 0.1 160 14.35 2 2 2 3 4 G690D A1598D 74/42 36 0.0125 142.5 0 3 3 3 3 4 N96H N96H 75/43 45 0.2 214.5 11.7 2 1 2 1 3 IVS35þ2t > c G1961E 77/44 19 0.34 137.5 11.75 2 1 - 1 3 G1961E G618R 81/45 66 0.335 163 2 - 3 - 2 4 N96D G1961E 82/46 41 0.1 116.5 0.15 3 3 3 3 4 4538insC IVS40þ5g > a 83/47 17 0.395 165 19.25 1 1 1 1 2 G1961E IVS45þ1g > c 84/47 26 0.135 120 16.2 2 1 2 1 3 G1961E IVS45þ1g > c 85/48 10 0.16 149.5 12.4 2 2 2 1 3 IVS35þ2t > c IVS40þ5g > a 87/40 25 0.9 155 15 2 1 2 1 2 N96D L2140Q 88/49 32 0.0715 144 0.1 - 3 - 3 4 IVS45þ1g > c R2149X 89/50 14 0.1185 147 1.85 3 1 - 3 4 P402A 250insCAAA 90/51 35 0.07 116.5 0 - 3 - 3 4 A1598D R2030X 94/52 30 0.1 144 12.85 2 1 - 1 1 A1598D G1961E Fam, family; OCT ft, optical coherence tomography foveal thickness; MP, microperimetry; IS/OS, inner-outer segment junction; FAF, fundus autofluorescence; ERG, electroretinogram; mfERG, multifocal-electroretinogram. Login to comment
67 Clinical and Molecular Data of STGD Patients Patient ID/Fam Age (y) Visual Acuity OCT ft (lm) MP (dB) IS/OS* Fundusߤ FAFߥ ERG&#a7; mfERGjj Mutation 1 Mutation 2 4/2 50 0.0715 134 5.25 - 1 - 2 4 G1961E 250InsCAAA 5/2 47 0.1 127 14.2 2 1 1 1 3 G1961E 250InsCAAA 6/3 33 0.05 125 9.8 2 2 2 1 3 G1961E R2149X 7/4 18 0.085 135 0 - 2 - 3 4 5917del G 5917del G 8/5 16 0.095 104 0.9 3 2 3 3 4 L541P; A1038V L541P; A1038V 9/6 71 0.03 109 0 3 3 3 2 4 IVS35&#fe;2t > c G1961E 11/7 46 0.2 137 9.35 2 1 2 1 1 Y850K A1598D 13/8 35 0.017 163 0 - 3 - 3 4 L541P R1098C 15/10 20 0.1 135.5 11.05 2 1 1 1 4 IVS35&#fe;2t > c G1961E 16/11 20 0.47 96 16.7 2 1 2 1 2 L541P; A1038V L541P; A1038V 17/11 34 0.1 114.5 7.55 2 1 2 1 3 L541P; A1038V L541P; A1038V 18/11 18 1 134 16.15 1 1 1 1 3 L541P; A1038V L541P; A1038V 19/12 12 0.12 242 6.5 3 1 2 1 2 L541P; A1038V L541P; A1038V 20/13 28 0.1 111 14.2 2 2 2 1 3 R1443H IVS35&#fe;2t > c 21/14 34 0.2 152 14.15 2 1 2 2 4 R653C G1961E 22/15 69 0.079 122 0 3 3 3 3 4 I1562T R2149X 23/15 46 0.55 162 1.05 3 3 3 3 4 I1562T IVS45&#fe;1g > c 25/16 28 0.11 105.5 3.1 3 2 2 3 4 R212C R212C 26/17 13 0.084 138.5 0.2 3 2 3 1 3 R18W C1490Y 27/4 20 0.0775 131 0 - 3 - 3 4 5917del G 5917del G 28/4 23 0.042 159.5 0 - 3 - 3 4 5917del G 5917del G 30/18 29 0.0375 103 0 3 3 3 3 4 N965S G1961E 31/19 17 0.1 102 9 3 2 2 3 4 L541P F655C 38/20 20 0.225 95 16 2 1 1 3 4 L541P G1961E 39/21 20 0.17 146 16.7 2 1 1 1 3 G1961E R2030X 42/22 43 0.575 127 7.05 2 1 2 1 2 250insCAAA G1961E 43/23 12 0.1 117.5 11.55 2 2 2 1 3 IVS40&#fe;5g > a IVS15-8g > a 44/24 29 0.1 149 18.5 2 1 2 1 3 G1961E 4736del6bpins2bp 46/25 38 0.0075 182.5 0 - 3 - 3 4 G618R G1972R 48/26 35 0.46 133.5 12.25 2 1 - 1 3 4538insC G1961E 50/27 13 0.2 122.5 17.35 2 1 2 1 3 IVS35&#fe;2t > c G1961E 51/28 24 0.065 123 0 3 3 3 3 4 250InsCAAA V767D 52/29 14 1 147 6.15 1 1 1 3 4 L2027F A1881V 53/30 45 0.1 120 6.05 3 2 2 1 3 G1961E R2030X 54/30 24 0.09 159 2.65 3 3 3 3 4 V767D R2030X 55/31 34 0.085 150 5.15 3 3 3 3 4 N96H IVS40&#fe;5g > a 56/32 48 0.0335 118.5 4.4 - 3 - 2 4 IVS35&#fe;2t > c G1961E 58/32 52 0.05 124 5.8 3 2 2 2 4 IVS35&#fe;2t > c G1961E 60/33 43 0.065 163 15.95 2 1 - 1 2 250InsCAAA G1961E 61/34 45 0.03 187.5 4.5 1 1 1 2 1 R1640Q G1961E 64/35 33 0.0665 158 0 3 3 3 3 4 C2150R 2626InsTTT 65/35 38 0.008 172 0.05 3 3 3 3 4 C2150R 2626InsTTT 66/36 42 0.4 137 0.95 3 2 2 1 3 N96D IVS40&#fe;5g > a 67/37 14 0.235 132 0.15 3 2 3 3 4 IVS6-2a > t IVS6-2a > t 69/38 19 0.09 120 0 3 1 2 1 3 R511H N529S 70/39 42 0.515 140 0.4 3 3 3 3 4 IVS40&#fe;5g > a N965S 72/40 33 0.096 116.5 5.1 3 2 2 1 3 N96D L2140Q 73/41 17 0.1 160 14.35 2 2 2 3 4 G690D A1598D 74/42 36 0.0125 142.5 0 3 3 3 3 4 N96H N96H 75/43 45 0.2 214.5 11.7 2 1 2 1 3 IVS35&#fe;2t > c G1961E 77/44 19 0.34 137.5 11.75 2 1 - 1 3 G1961E G618R 81/45 66 0.335 163 2 - 3 - 2 4 N96D G1961E 82/46 41 0.1 116.5 0.15 3 3 3 3 4 4538insC IVS40&#fe;5g > a 83/47 17 0.395 165 19.25 1 1 1 1 2 G1961E IVS45&#fe;1g > c 84/47 26 0.135 120 16.2 2 1 2 1 3 G1961E IVS45&#fe;1g > c 85/48 10 0.16 149.5 12.4 2 2 2 1 3 IVS35&#fe;2t > c IVS40&#fe;5g > a 87/40 25 0.9 155 15 2 1 2 1 2 N96D L2140Q 88/49 32 0.0715 144 0.1 - 3 - 3 4 IVS45&#fe;1g > c R2149X 89/50 14 0.1185 147 1.85 3 1 - 3 4 P402A 250insCAAA 90/51 35 0.07 116.5 0 - 3 - 3 4 A1598D R2030X 94/52 30 0.1 144 12.85 2 1 - 1 1 A1598D G1961E Fam, family; OCT ft, optical coherence tomography foveal thickness; MP, microperimetry; IS/OS, inner-outer segment junction; FAF, fundus autofluorescence; ERG, electroretinogram; mfERG, multifocal-electroretinogram. Statistics Our set of data is described by continuous (BCVA, OCT foveal thickness, and macular sensitivities) and categorical (fundus, FAF, IS/ OS, ERG, and mfERG groups) variables. Login to comment

PMID: 22466470 [PubMed] Leng T et al: "Foveal cavitation as an optical coherence tomography finding in central cone dysfunction."

No. Sentence Comment

88 Previous reports by Cella et al10 and by Gomes et al11 describe cases of ABCA4 mutations involving L541P/ A1038V and G1961E. Login to comment
90 Cella et al10 proposed that the G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region; however, this mutation was present as a heterozygous mutation in only 2 of 5 cases tested (Cases 4 and 5) and L541P/A1038V was not present. Login to comment

PMID: 22427542 [PubMed] Fritsche LG et al: "A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene."

No. Sentence Comment

71 The heterozygous change c.3113C>T (p.A1038V) was found in five patients together with c.1622T>C (p.L541P) and in another two patients together with c.3261A>C (p.E1087D, patient L-099-GA) and c.3752delA (p.E1251fs, patient H-144-GA), respectively. Login to comment
88 The patient carries a heterozygous, complex disease allele (c.1622T>C, p.L541P; c.3113C>T, p.A1038V) in the ABCA4 gene. Login to comment
120 In this context, it may be of interest that the complex allele L541P/ A1038V was found in 5/20 GPS[+] alleles. Login to comment
69 The heterozygous change c.3113C>T (p.A1038V) was found in five patients together with c.1622T>C (p.L541P) and in another two patients together with c.3261A>C (p.E1087D, patient L-099-GA) and c.3752delA (p.E1251fs, patient H-144-GA), respectively. Login to comment
86 The patient carries a heterozygous, complex disease allele (c.1622T>C, p.L541P; c.3113C>T, p.A1038V) in the ABCA4 gene. Login to comment
118 In this context, it may be of interest that the complex allele L541P/ A1038V was found in 5/20 GPS[+] alleles. Login to comment

PMID: 22247458 [PubMed] Cideciyan AV et al: "Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trials."

No. Sentence Comment

42 Clinical and Molecular Characteristics of the ABCA4 Patients Patient Age (y)/Sex ABCA4 Mutation Clinical Diagnosis Visual Acuity* Kinetic Visual Field Extent (V-4e)†Allele 1 Allele 2 Foveal Fixation P1‡ 12/M N965S W821R STGD 20/20 97 P2‡ 17/F V989A IVS28ϩ5 GϾT STGD 20/100 90 P3 18/M G1961E R1129L§ STGD 20/100 105 P4 21/F R212C P68R STGD 20/125 101 P5 24/M P1511 del1ccgC R1705Q STGD 20/25 114 P6 31/M G863A R1108C STGD 20/25 105 P7 32/F IVS40ϩ5 GϾA V935A STGD 20/32 103 P8 34/M G1961E - CRD 20/32 98 P9 37/F R681X P309R STGD 20/20 109 P10 39/M G1961E C54Y§ STGD 20/40 101 P11‡ 42/F G1961E V256V STGD 20/32 105 P12‡ 46/F G1961E V256V STGD 20/32 106 P13 52/F G1961E P1380L STGD 20/40 105 P14 58/M D600E R18W§ STGD 20/40 84 Extrafoveal Fixation P15 11/M V256V T1526M CRD 20/200 102 P16 15/M C54Y IVS35ϩ2 TϾC STGD 20/200 96 P17‡ 16/F V989A IVS28ϩ5 GϾT STGD 20/100 100 P18‡ 16/M N965S W821R STGD 20/125 100 P19 19/F A1038V/L541P N965S STGD 20/400 90 P20 21/M G863A IVS35ϩ2 TϾC STGD 20/200 99 P21 22/F G1961E R152X STGD 20/50 104 P22 27/M G863A P1660S§ STGD 20/100 98 P23 27/F G1961E A1038V/L541P STGD 20/100 109 P24 29/M G1961E T1019M STGD 20/100 104 P25 33/M P1486L deletion of exon 7 STGD 20/400 98 P26 36/F G863A C1490Y STGD 20/100 93 P27 41/M A1038V/L541P - STGD 20/125 108 P28 49/F T1526M R2030Q STGD 20/125 98 P29 55/F W855X - STGD 20/160 87 P30 56/F G1961E IVS37ϩ1 GϾA§ STGD 20/125 89 P31 60/F G1961E M669 del2ccAT STGD 20/125 104 STGD, Stargardt disease; CRD, cone-rod dystrophy. Login to comment

PMID: 22229821 [PubMed] Duno M et al: "Phenotypic and genetic spectrum of Danish patients with ABCA4-related retinopathy."

No. Sentence Comment

56 Table 1 Mutations identified by HRM in the initial 50 heterozygous patients Patient Mutation 1 (Asper) Mutation 2 (HRM) RefDNA Protein Exon/intron DNA Protein Exon/intron D043 c.2588G>C p.G863A 17 c.184 C>T p.P62S 3 New D069 c.3113C>T p.A1038V 21 c.1529 T>G p.L510R 11 New D050 c.2588G>C p.G863A 17 c.1529 T>G p.L510R 11 New D112 c.2894A>G p.N965S 19 c.1529 T>G p.L510R 11 New D099 c.6089G>A p.R2030Q 44 c.1529 T>G p.L510R 11 New D165 c.1822T>C p.F608L 13 c.2243 G>A p.C748Y 15 New D166 c.2588G>C p.G863A 17 c.2300 T>A p.V767D 15 Known D117 c.3191-2A>G na IVS21 c.2408delG na 16 New D135 c.2894A>G p.N965S 19 c.2408delG na 16 New D147 c.2894A>G p.N965S 19 c.2408delG na 16 New D173 c.4469G>A p.C1490Y 30 c.2915C>A p.T972N 19 Known D013* c.1622C>T p.L541P 12 c.1313C>T p.A1038V 21 Known D181 c.6089G>A p.R2030Q 44 c.3380 G>A p.G1127E 23 New D018 c.6449G>A p.C2150Y 47 c.3736 C>G p.L1246V 25 New D191 c.2588G>C p.G863A 17 c.4069 G>A p.A1357T 27 New D167 c.5461-10T>C na IVS38 c.4102 C>T p.R1368C 27 New D022 c.4462T>C p.C1488R 30 c.4102 C>T p.R1368C 27 New D108 c.1648G>A p.G550R 12 c.4102 C>T p.R1368C 27 New D414 c.2588G>C p.G863A 17 c.4653 G>A p.W1551X 32 New D027 c.2588G>C p.G863A 17 c.4668-2A>G na IVS32 New D136 c. Login to comment
58 [1622C>T+3113C>T] p.[L541P+A1038V] 12 c.5584 + 1G>A na IVS39 New D188 c.5461-10T>C na IVS38 c.5693G>A p.R1898H 40 Known D433 c.5882G>A p.G1961E 42 c.6005 + 1G>A na IVS43 Known D134 c.4667 + 2G>T na IVS32 c.6098 T>G p.L2033R 44 New D186 c.3322C>T p.R1108C 22 c.6386 + 1G>A na IVS46 New D182 c.6089G>A p.R2030Q 44 c.6386 + 1G>A na IVS46 New D189 c.2894A>G p.N965S 19 c.6478 A>G p.K2160E 47 New *p.L541P and p.A1038V might be located on the same allele. Login to comment

PMID: 22328824 [PubMed] Roberts LJ et al: "Stargardt macular dystrophy: common ABCA4 mutations in South Africa--establishment of a rapid genetic test and relating risk to patients."

No. Sentence Comment

139 of alleles detected Frequency p.Cys54Tyr c. 161 G>A 2 0.55% p.Arg152* c. 454 C>T 12 3.31% p.Arg152Gln c. 455 G>A 3 0.83% p.Gly172Ser c. 514 G>A 1 0.28% p.Arg212Cys c. 634 C>T 1 0.28% p.Lys223Gln c. 667 A>C 1 0.28% p.V256V (Splice) c. 768 G>T 18 4.97% p.Pro291Leu c. 872 C>T 1 0.28% p.Trp439* c. 1317 G>A 1 0.28% p.Ala538Asp c. 1613 C>A 1 0.28% p.Leu541Pro c. 1622 T>C 1 0.28% p.Arg602Trp c. 1885C>T 30 8.29% p.Val643Met c. 1927 G>A 1 0.28% p.Arg653Cys c. 1957 C>T 1 0.28% p.Arg681* c. 2041 C>T 3 0.83% p.Val767Asp c. 2300 T>A 1 0.28% p.Trp855* c.2564_2571delGGTACCTT 2 0.55% p.Gly863Ala c. 2588 G>C 11 3.04% p.Val931Met c. 2791 G>A 1 0.28% p.Asn965Ser c. 2894 A>G 4 1.10% p.Val989Ala c. 2966 T>C 1 0.28% p.Gly991Arg c. 2971 G>C 1 0.28% p.Thr1019Met c. 3056 C>T 1 0.28% p.Ala1038Val c. 3113 C>T 3 0.83% p.Glu1087Lys c. 3259 G>A 1 0.28% p.Arg1108Cys c. 3322 C>T 2 0.55% p.Leu1201Arg c. 3602 T>G 4 1.10% p.Arg1300Gln c. 3899 G>A 4 1.10% p.Pro1380Leu c. 4139 C>T 3 0.83% p.Trp1408Arg c. 4222 T>C 1 0.28% - c. 4253+5G>A 1 0.28% p.Phe1440Ser c. 4319 T>C 1 0.28% p.Arg1443His c. 4328 G>A 1 0.28% p.Cys1490Tyr c.4469 G>A 54 14.92% p.Gln1513Pro fs*42 c. 4535 insC 1 0.28% p.Ala1598Asp c. 4793C>A 1 0.28% p.Arg1640Trp c. 4918 C>T 2 0.55% p.Ser1642Arg c. 4926 C>G 1 0.28% p.V1681_C1685del c. 5041 del15 1 0.28% - c. 5461-10T>C 24 6.63% - c. 5714+5 G>A 2 0.55% p.Pro1948Leu c. 5843 C>T 1 0.28% p.Gly1961Glu c. 5882 G>A 4 1.10% p.Leu2027Phe c.6079 C>T 30 8.29% p.Arg2030* c. 6088 C>T 1 0.28% p.Arg2030Gln c. 6089 G>A 3 0.83% p.Arg2038Trp c. 6112 C>T 1 0.28% p.Arg2107His c. 6320 G>A 2 0.55% p.Arg2118Glu fs*27 c. 6352 delA 1 0.28% p.Cys2150Tyr c. 6449 G>A 1 0.28% p.Gln2220* c. 6658 C>T 1 0.28% p.Gly863Ala mutation, which appears to have a founder effect in the Netherlands [13,15], the results obtained from the current study are in agreement with September et al.`s conclusions [9]. Login to comment

PMID: 22312191 [PubMed] Burke TR et al: "Familial discordance in Stargardt disease."

No. Sentence Comment

28 DISCUSSION Both patients 1 and 2 were compound heterozygous for the W663X and A1038V mutations in the ABCA4 gene. Login to comment
29 W663X was previously reported as a disease-causing mutation [9]; it likely results in a completely dysfunctional protein due to the stop codon in the first 1/4 of the gene. A1038V, a missense mutation, is usually reported as a component of the complex allele L541P/A1038V, one of the most commonly detected mutations in the ABCA4 gene. A1038V is also known to be pathogenic without L541P as it has a deleterious effect on ATPase by ABCA4 in vitro [10,11]. Login to comment
33 All affected patients in this family carried the W663X mutation, and although G1961E is considered a "mild" mutation, both patients with the G1961E mutation had earlier ages of onset than those with A1038V, which is considered "severe." Login to comment
34 A report by Cideciyan et al. describing age of disease onset in terms of "age of retina-wide disease initiation" (ADI) suggested that the G1961E mutation results in a much later ADI than the complex allele L541P/A1038V [18]. Login to comment

PMID: 22076985 [PubMed] Lazow MA et al: "Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP)."

No. Sentence Comment

59 Characteristics of Patients with STGD Patient ID Eye Age Sex BCVA Mutation(s) (ABCA4) P8 12 OS 33 F 20/150 G1961E P9 2 OS 30 M 20/150 T1253M, G1961E P10 9817 OS 21 F 20/63 * P11 9 OS 19 M 20/150 IVS20ϩ5 GϾA, G1961E P12 6953 OD 49 F 20/50 * P13 11 OS 59 M 20/100 P1380L, S1696N P14 9831 OD 28 M 20/500 * P15 8813 OD 13 M 20/50 * P16 8 OS 34 M 20/100 G1961E, G1961E P17 6.1 OD 24 F 20/200 L541P/A1038V, G1961E P18 8833 OS 13 F 20/160 N965S, L2229P P19 8938 OD 13 M 20/200 A192T, R1300Q P20 5470 OD 28 F 20/100 * P21 9901 OS 41 M 20/160 I32V P22 9327 OS 11 F 20/63 G863A, A1695D P23 9386 OS 18 M 20/40 * P24 8862 OD 30 F 20/63 * P25 6.1 OD 21 F 20/150 L541P/A1038V, G1961E P26 6.2 OS 18 F 20/70 L541P/A1038V, G1961E P27 10 OS 23 F 20/150 L541P/A1038V, I1846T * Patient did not undergo genetic testing. Login to comment
31 Characteristics of Patients with STGD Patient ID Eye Age Sex BCVA Mutation(s) (ABCA4) P8 12 OS 33 F 20/150 G1961E P9 2 OS 30 M 20/150 T1253M, G1961E P10 9817 OS 21 F 20/63 * P11 9 OS 19 M 20/150 IVS20af9;5 Gb0e;A, G1961E P12 6953 OD 49 F 20/50 * P13 11 OS 59 M 20/100 P1380L, S1696N P14 9831 OD 28 M 20/500 * P15 8813 OD 13 M 20/50 * P16 8 OS 34 M 20/100 G1961E, G1961E P17 6.1 OD 24 F 20/200 L541P/A1038V, G1961E P18 8833 OS 13 F 20/160 N965S, L2229P P19 8938 OD 13 M 20/200 A192T, R1300Q P20 5470 OD 28 F 20/100 * P21 9901 OS 41 M 20/160 I32V P22 9327 OS 11 F 20/63 G863A, A1695D P23 9386 OS 18 M 20/40 * P24 8862 OD 30 F 20/63 * P25 6.1 OD 21 F 20/150 L541P/A1038V, G1961E P26 6.2 OS 18 F 20/70 L541P/A1038V, G1961E P27 10 OS 23 F 20/150 L541P/A1038V, I1846T * Patient did not undergo genetic testing. Login to comment

PMID: 21873672 [PubMed] Burke TR et al: "Quantification of peripapillary sparing and macular involvement in Stargardt disease (STGD1)."

No. Sentence Comment

117 TABLE1.SummaryofClinical,Demographic,andGeneticData PatientSex Ageat Exam(y)EyeVA BCEA1SD (deg2 ) Eccentricity ofPRL(deg) ERG Group FAFAbnormalities Allele1Allele2Allele3DistributionPeripapillaryArea 1F43OS20/200.730IIM-A1799DNDND 2M30OS20/1503.216IM-T1253MG1961END 3F55OD20/301.820IEM-G863AIVS28ϩ5GϾTND 4M44OD20/250.650IM-E161KNDND 5.1F24OD20/2001.571IM-L541P/A1038VG1961END 5.2F22OD20/302.741IM-L541P/A1038VG1961END 6.1F21OD20/1502.011IM-L541P/A1038VG1961END 6.2F18OS20/1003.094IM-L541P/A1038VG1961END 7F27OS20/4002.979*IIEMPeripapillaryatrophyL2027FG851DND 8M34OS20/1002.164IM-G1961EG1961END 9M20OS20/1502.774IM-IVS20ϩ5GϾAG1961END 10F23OS20/1509.055IM-L541P/A1038VI1846TND 11M59OS20/1006.5210IIEM-P1380LS1696NND 12M49OD20/1509.971IEMNasalϩtemporalflecksR1108HP1380LND 13M47OS20/805.627IEM-G863AY106XND 14F42OD20/2009.539IEMTemporalflecksN965SNDND 15M14OD20/20023.841IIEMNasalflecksIVS38-10TϾCIVS40ϩ5GϾAND 16M52OS20/201.30IM-IVS38-10TϾCNDND 17M34OS20/302.81IM-L541P/A1038VG1961END 18F33OD20/10066IM-G1961ER2077WND 19F22OS20/60114IM-A854TA1038VC2150Y 20F34OS20/20014.214IEM-G1961ENDND 21F19OD20/2003.712IEM-R602WM18821ND 22F27OD20/4009.69IIEMPeripapillaryatrophyP1380LP1380LND 23F18OS20/504.95IEM-R1640WV1693IND 24M22OS20/15010.52IEM-C54YNDND 25M44OS20/1509.15IEM-R1640WNDND VA,visualacuity;Rel.Unstable,relativelyunstablefixation;FAFAbn,fundusautofluorescenceabnormalities;M,macularonly;EM,extramacular;N,nasal;T,temporal;ND,notdetected. Login to comment
112 Summary of Clinical, Demographic, and Genetic Data Patient Sex Age at Exam (y) Eye VA BCEA 1 SD (deg 2 ) Eccentricity of PRL (deg) ERG Group FAF Abnormalities Allele 1 Allele 2 Allele 3 Distribution Peripapillary Area 1 F 43 OS 20/20 0.73 0 II M - A1799D ND ND 2 M 30 OS 20/150 3.21 6 I M - T1253M G1961E ND 3 F 55 OD 20/30 1.82 0 I EM - G863A IVS28af9;5 Gb0e;T ND 4 M 44 OD 20/25 0.65 0 I M - E161K ND ND 5.1 F 24 OD 20/200 1.57 1 I M - L541P/A1038V G1961E ND 5.2 F 22 OD 20/30 2.74 1 I M - L541P/A1038V G1961E ND 6.1 F 21 OD 20/150 2.01 1 I M - L541P/A1038V G1961E ND 6.2 F 18 OS 20/100 3.09 4 I M - L541P/A1038V G1961E ND 7 F 27 OS 20/400 2.97 9* II EM Peripapillary atrophy L2027F G851D ND 8 M 34 OS 20/100 2.16 4 I M - G1961E G1961E ND 9 M 20 OS 20/150 2.77 4 I M - IVS20af9;5 Gb0e;A G1961E ND 10 F 23 OS 20/150 9.05 5 I M - L541P/A1038V I1846T ND 11 M 59 OS 20/100 6.52 10 II EM - P1380L S1696N ND 12 M 49 OD 20/150 9.97 1 I EM Nasalaf9;temporal flecks R1108H P1380L ND 13 M 47 OS 20/80 5.62 7 I EM - G863A Y106X ND 14 F 42 OD 20/200 9.53 9 I EM Temporal flecks N965S ND ND 15 M 14 OD 20/200 23.84 1 II EM Nasal flecks IVS38-10 Tb0e;C IVS40af9;5 Gb0e;A ND 16 M 52 OS 20/20 1.3 0 I M - IVS38-10 Tb0e;C ND ND 17 M 34 OS 20/30 2.8 1 I M - L541P/A1038V G1961E ND 18 F 33 OD 20/100 6 6 I M - G1961E R2077W ND 19 F 22 OS 20/60 11 4 I M - A854T A1038V C2150Y 20 F 34 OS 20/200 14.2 14 I EM - G1961E ND ND 21 F 19 OD 20/200 3.7 12 I EM - R602W M18821 ND 22 F 27 OD 20/400 9.6 9 II EM Peripapillary atrophy P1380L P1380L ND 23 F 18 OS 20/50 4.9 5 I EM - R1640W V1693I ND 24 M 22 OS 20/150 10.5 2 I EM - C54Y ND ND 25 M 44 OS 20/150 9.1 5 I EM - R1640W ND ND VA, visual acuity; Rel. Login to comment

PMID: 20696155 [PubMed] Burke TR et al: "Loss of peripapillary sparing in non-group I Stargardt disease."

No. Sentence Comment

184 Also, the type of involvement of the peripapillary area Table 1 Summary of clinical and genetic information for patients with ERG Group I Stargardt Disease. Case Mutation Mutation OA Duration Age at AF Visual Acuity Flecks Atrophy GA (mm2 ) PPA # Sex Allele 1 Allele 2 PPA (years) (years) (years) OD OS OD OS OD OS OD OS Pattern RON 1 Male G1961E G1961E e 19 13 32 20/70 20/70 M M M M 1.6 0.2 None 2 Female G1961E *IVS43 þ 1 G > T e 8 21 27 20/200 20/200 M M M M na na None 3.1 Male L541P/A1038V G1961E e 28 3 31 20/50 20/30 M M M M na na None 3.2 Male L541P/A1038V G1961E e 28 5 33 20/60 20/50 M M M M na na None 4.1 Female L541P/A1038V G1961E e 14 3 17 20/30 20/25 None None None None na na None 4.2 Female L541P/A1038V G1961E e 14 10 24 20/150 20/200 M M M M na na None 5 Female G1961E R2077W e 25 5 30 20/60 20/50 None None M M na na None 6.1 Female G1961E L541P/A1038V e 18 3 21 20/150 20/150 None None M M na na None 6.2 Female G1961E L541P/A1038V e 15 3 18 20/150 20/150 None None M M na na None 7 Female R602Q R602Q e 31 5 36 20/20 20/60 M,EM M,EM M M 0.7 0.3 None 8 Male L541P/A1038V ND e 22 24 46 20/200 20/200 M M M M 13.2 4.1 None 9 Femlae A1038V ND e 27 10 37 20/100 20/60 M,EM M,EM M M na na None 10 Female G1961E ND e 27 6 33 20/150 20/150 M M M M na na None 11 Female G1961E ND e 43 24 67 20/40 20/200 M M M M 4.8 na None 12 Male R212C ND OU 5 23 28 20/200 20/200 M,EM M,EM M M 1.6 4.2 Patchy N,T Abbreviations: ERG, electroretinogram; PPA, peripapillary atrophy; OD, right eye; OS, left eye; OU, both eyes; OA, onset age; AF, autofluoresence; M, macula; EM, extramacular retina; GA, geographic atrophy; na, not available; RON, relation to optic nerve; N, nasal; T, temporal; ND, mutation was not detected by the ABCR array e suggesting the presence of a currently unknown mutant allele; and *newly described mutation. Login to comment
185 Table 2 Summary of clinical and genetic information for patients with ERG Groups II or III Stargardt Disease. Case Mutation Mutation ERG OA Duration Age at AF Visual Acuity Flecks GA position GA (mm2) PPA # Sex Allele 1 Allele 2 PPA Group (years) (years) (years) OD OS OD OS OD OS OD OS Pattern RON 13 Female P1380L R1640Q OU II 11 24 35 HM HM EM EM M,EM M,EM na na Scalloped - 14 Male IVS38-10 T>C IVS40+5 G>A OU II 7 6 13 20/150 20/150 M,EM M,EM M M na na Flecks N 15 Female M1 V/R2030Q P1380L OU II 8 10 18 20/150 20/150 M,EM M,EM M M 3.52 na Patchy N,T 16 Female P1380L P1380L OU II 18 8 26 20/400 20/400 M,EM M,EM M M 0.25 na Patchy N,T 17 Female L541P/A1038 V L2027F OU II 10 22 32 CF CF M,EM M,EM M M 11.7 5.1 Patchy N,T 18 Male A1773 V ND OU II 35 6 41 CF 20/30 M,EM M,EM M M 4.2 3.7 Patchy N,T 19 Female L2027F ND OU I/II 10 17 27 20/400 20/400 M,EM M,EM M M 1.6 0.1 Patchy N,T 20 Male R602 W R1300X OU III 8 18 26 CF CF None None M,EM M,EM na na Scalloped N,T 21 Female C54Y IVS14+1 G>C OU III 8 55 63 CF HM EM None M,EM M,EM na na Complete - 22.1 Male 4537delC *R107X OU III 5 8 13 20/200 20/200 EM EM M M 2.3 1.7 Patchy N,T 22.2 Female 4537delC *R107X - III 6 2 8 20/200 20/200 M,EM M,EM M M na na - - 23 Male P1380L IVS40+5 G>A OU III 29 26 55 20/400 20/400 EM EM M,EM M,EM na na Complete - 24 Male A1598D A1598D OU III 13 40 53 20/400 20/400 NA NA M,EM M,EM na na Scalloped N,T 25 Male G172S ND OU III 25 7 32 CF CF None None M,EM M,EM na na Complete - 26 Female R1108C ND OU III 9 50 59 20/400 20/400 EM EM M,EM M,EM na na Complete - 27 Male V767D ND OD III 5 10 15 20/400 20/400 EM EM M M na na Patchy T 28 Male P1380L ND OU II/III 9 21 30 20/400 20/400 EM EM M M na na Patchy N,T Abbreviations: ERG, electroretinogram; PPA, peripapillary atrophy; OD, right eye; OS, left eye; OU, both eyes; OA, onset age; AF, autofluoresence; M, macula; EM, extramacular retina; GA, geographic atrophy; na, not available; RON, relation to optic nerve; N, nasal; T, temporal; ND, mutation was not detected by the ABCR array, suggesting the presence of a currently unknown mutant allele; and *newly described mutation. Login to comment
183 Also, the type of involvement of the peripapillary area Table 1 Summary of clinical and genetic information for patients with ERG Group I Stargardt Disease. Case Mutation Mutation OA Duration Age at AF Visual Acuity Flecks Atrophy GA (mm2 ) PPA # Sex Allele 1 Allele 2 PPA (years) (years) (years) OD OS OD OS OD OS OD OS Pattern RON 1 Male G1961E G1961E e 19 13 32 20/70 20/70 M M M M 1.6 0.2 None 2 Female G1961E *IVS43 &#fe; 1 G > T e 8 21 27 20/200 20/200 M M M M na na None 3.1 Male L541P/A1038V G1961E e 28 3 31 20/50 20/30 M M M M na na None 3.2 Male L541P/A1038V G1961E e 28 5 33 20/60 20/50 M M M M na na None 4.1 Female L541P/A1038V G1961E e 14 3 17 20/30 20/25 None None None None na na None 4.2 Female L541P/A1038V G1961E e 14 10 24 20/150 20/200 M M M M na na None 5 Female G1961E R2077W e 25 5 30 20/60 20/50 None None M M na na None 6.1 Female G1961E L541P/A1038V e 18 3 21 20/150 20/150 None None M M na na None 6.2 Female G1961E L541P/A1038V e 15 3 18 20/150 20/150 None None M M na na None 7 Female R602Q R602Q e 31 5 36 20/20 20/60 M,EM M,EM M M 0.7 0.3 None 8 Male L541P/A1038V ND e 22 24 46 20/200 20/200 M M M M 13.2 4.1 None 9 Femlae A1038V ND e 27 10 37 20/100 20/60 M,EM M,EM M M na na None 10 Female G1961E ND e 27 6 33 20/150 20/150 M M M M na na None 11 Female G1961E ND e 43 24 67 20/40 20/200 M M M M 4.8 na None 12 Male R212C ND OU 5 23 28 20/200 20/200 M,EM M,EM M M 1.6 4.2 Patchy N,T Abbreviations: ERG, electroretinogram; PPA, peripapillary atrophy; OD, right eye; OS, left eye; OU, both eyes; OA, onset age; AF, autofluoresence; M, macula; EM, extramacular retina; GA, geographic atrophy; na, not available; RON, relation to optic nerve; N, nasal; T, temporal; ND, mutation was not detected by the ABCR array e suggesting the presence of a currently unknown mutant allele; and *newly described mutation. Login to comment

PMID: 20647261 [PubMed] Schindler EI et al: "Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population."

No. Sentence Comment

54 Allele VF model Acuity model Occurrences Groupa Leu2027Phe 22.81 0.14 4 a Leu1201Arg 22.29 0.16 2 a Met316fs 20.71 20.15 4 a Gly1961Glu 18.08 0.26 8 a Gly863Ala 16.54 0.36 19 a Pro1380Leu 15.88 0.39 10 a Ala1038Val 15.19 20.03 12 a Leu541Pro 10.95 0.08 1 b Asn965Ser 9.3 0.07 3 b IVS40 + 5 9.29 0.22 9 b Val256Val 9.27 0.84 2 b Phe608Ile 7.24 0.48 2 b IVS38-10 5.75 0.37 14 b Arg1108Cys 1.29 0.81 6 b Leu1430fs 0.37 0.6 2 b Arg2077Trp 26.89 0.93 4 b a When analyzed as groups, A alleles have significantly milder effects on both visual acuity (P , 1023 ) and visual field (P , 1027 ) than B alleles (see text). Login to comment
57 Allele VF model Acuity model Occurrences Groupa Leu2027Phe 22.81 0.14 4 a Leu1201Arg 22.29 0.16 2 a Met316fs 20.71 20.15 4 a Gly1961Glu 18.08 0.26 8 a Gly863Ala 16.54 0.36 19 a Pro1380Leu 15.88 0.39 10 a Ala1038Val 15.19 20.03 12 a Leu541Pro 10.95 0.08 1 b Asn965Ser 9.3 0.07 3 b IVS40 + 5 9.29 0.22 9 b Val256Val 9.27 0.84 2 b Phe608Ile 7.24 0.48 2 b IVS38-10 5.75 0.37 14 b Arg1108Cys 1.29 0.81 6 b Leu1430fs 0.37 0.6 2 b Arg2077Trp 26.89 0.93 4 b a When analyzed as groups, A alleles have significantly milder effects on both visual acuity (P , 1023 ) and visual field (P , 1027 ) than B alleles (see text). Login to comment

PMID: 20398653 [PubMed] Chen B et al: "Analysis of autofluorescent retinal images and measurement of atrophic lesion growth in Stargardt disease."

No. Sentence Comment

82 ID# Age Years followed Visual Acuity AL Area (mm2 ) HF Area (mm2 ) ffERG Amplitudes (mV) ffERG IT (msec) ABCA4 Variants OD OS OD OS OD OS OD OS OD OS Rod Cone Rod Cone Rod Cone Rod Cone AI AII Group A S0047 53 2.83 20/40 20/40 31.60 33.85 0.20 0.07 304.0 125.4 392.9 143.3 69.5 29.3 72.7 29.3 NF NF S0023 49 3.26 20/160 20/160 9.92 12.67 1.24 1.49 292.1 52.2 272.4 46.4 77.9 36.8 78.3 35.2 L541P/A1038V NF S0050 78 2.71 20/250 20/160 2.02 0.07 1.21 0.67 355.0 82.2 373.1 87.2 76.7 34.1 76.7 34.8 S2255I IVS5,þ1,G > C S0045 44 3.16 20/200 20/160 17.27 44.72 NM NM 177.0 55.7 201.9 50.0 85.3 41.5 87.7 39.9 L541P/A1038V R2107K S0018 35 2.28 20/200 20/250 4.31 2.53 NM NM ND ND ND ND ND ND ND ND G1961E S2255I S0033 63 2.35 20/800 20/400 15.51 12.09 1.30 0.22 168.2 53.0 180.9 45.4 96.3 38.0 101.0 38.4 R943Q IVS8,-9, T > C S0048 62 2.56 20/80 20/20 48.45 40.73 NM NM 119.7 69.5 213.9 54.6 71.2 35.6 80.6 35.2 R290Q K346T S0036 62 2.81 20/640 20/500 55.70 43.38 NM NM 174.8 41.1 158.1 50.8 106.6 38.5 102.3 35.2 R1129L Q234X S0029 62 2.81 20/40 20/80 57.62 61.25 NM NM 219.0 26.0 209.2 35.2 77.9 31.3 73.6 30.9 R2030Q NF S0024 43 3.20 20/25 20/25 4.91 3.91 4.18 1.48 98.2 23.7 148.0 36.2 84.0 33.2 85.5 33.6 NF NF S0078 35 1.17 20/100 20/125 5.64 5.39 0.70 0.83 230.1 106.7 187.6 108.8 71.2 34.1 64.6 34.1 IVS39-10,T > C NF S0032 64 2.56 20/250 20/320 8.67 3.67 0.67 0.74 273.2 75.5 235.1 114.7 87.9 30.5 72.7 30.1 R1108C L2027F S0051 52 1.90 20/25 20/20 32.78 29.23 NM NM ND ND ND ND ND ND ND ND E471K NF S0115 16 0.57 20/50 20/50 0.77 3.43 NM NM ND ND ND ND ND ND ND ND NF NF S0077 49 1.14 20/40 20/25 N/A 8.54 0.16 1.89 279.9 111.9 299.3 105.2 N/A N/A N/A N/A NF NF S0042 43 1.84 20/125 20/200 118.15 126.69 NM NM 122.3 27.7 114.8 29.3 85.7 36.4 89.6 36.0 S2255I E471K S0037 46 2.38 20/125 20/200 8.73 N/A 1.29 0.86 338.7 119.3 373.7 109.4 72.3 28.1 70.7 28.1 G1961E S2255I S0020 42 0.0 20/200 20/160 1.16 1.82 NM NM 140.4 43.2 159.9 45.8 81.3 31.3 71.5 29.3 NF NF S0041 44 0.0 20/200 20/160 4.73 7.09 0.96 1.36 260.5 65* 297.2 95.3 113.7 29.7 91.8 28.9 R1129L NF S0087 44 0.0 20/20 20/20 14.89 23.09 NM NM 180.9 66.8 182.2 78.0 76.1 32.9 72.2 32.9 IVS40, þ5,G > A NF S0053 43 0.0 20/100 20/160 1.33 1.85 NM NM ND ND ND ND ND ND ND ND S2255I NF S0097 73 0.0 20/200 20/200 49.21 54.26 NM NM ND ND ND ND ND ND ND ND D1532E NF S0080 28 0.0 20/125 20/200 NA 0.98 0.56 0.03 333.1 117.2 325.1 121.4 80.2 32.5 82.6 32.9 E1122K S2255I S0210 49 0.0 20/160 20/200 0.21 NA NM NM 304.1 76.1 425.7 81.1 72.8 33.7 79.8 33.7 NF NF Group B S0133 30 0.0 20/125 20/32 0.51 0.01 387.1 123.7 374.8 105.1 65.4 32.9 65.0 32.9 NF NF S0046 49 0.0 20/160 20/160 1.48 1.68 491.2 148.9 494.9 145.3 72.7 30.1 77.3 29.7 P1380L G1961E S0141 40 0.0 20/13 20/32 1.88 0.41 389.0 156.5 343.5 150.6 70.8 33.3 69.7 34.4 NF NF S0058 61 0.0 20/50 20/50 1.48 1.52 ND ND ND ND ND ND ND ND NF NF S0149 16 0.0 20/80 20/100 1.59 0.62 285.0 87.4 333.4 115.3 62.6 32.5 61.4 32.5 NF NF S0083 15 0.0 20/13 20/13 0.17 0.48 441.1 144.2 472.0 155.5 74.4 33.3 71.6 33.3 G863A NF S0216 44 0.0 20/25 20/32 0.52 1.04 228.7 97.7 192.7 75.3 83.8 36.8 85.7 36.0 NF NF S0076 9 0.0 20/200 20/160 3.70 4.23 557.7 139.5 319.8 117.3 81.6 29.7 73.4 28.9 W1408R T1526M S0021 19 0.0 20/160 20/160 1.81 1.08 390.4 202.1 ND ND 63.3 29.3 ND ND L2027F W31R S0085 35 0.0 20/16 20/20 2.70 2.56 ND ND ND ND ND ND ND ND C54T R219T S0044 30 0.0 20/250 20/250 4.23 3.77 ND ND ND ND ND ND ND ND A1794D L2027F S0035 47 0.0 20/160 20/125 0.46 0.13 239.6 112.3 325.0 141.6 64.1 28.1 62.5 28.1 G863A E471K S0065 61 0.0 20/100 20/125 0.83 0.15 243.4 58.6 226.5 49.2 74.8 32.9 84.5 33.3 G1961E NF S0213 27 0.0 20/25 20/25 0.99 1.03 384.2 124.4 424.4 137.9 72.4 31.7 72.4 35.2 NF NF S0088 55 0.0 20/25 20/20 0.11 0.47 ND ND ND ND ND ND ND ND R1898H NF S0127 16 0.0 20/63 20/63 0.08 0.69 536.3 128.9 470.3 136.4 65.4 30.9 77.1 30.9 L541P/A1038V NF S0057 47 0.48 20/125 20/160 1.20 1.75 252.1 80.3 210.5 100.5 75.5 32.9 89.6 32.5 NF NF S0043 53 2.91 20/200 20/200 0.97 0.53 250.5 173.2 354.6 179.2 72.7 28.5 80.1 30.1 G1961E F873I S0101 37 1.1 20/40 20/20 0.14 0.25 382.2 159.7 422.7 156.7 70.5 32.5 74.0 32.9 A1038V IVS42 þ 1,G > A S0027 17 2.18 20/50 20/50 1.60 2.12 196.3 36.3 198.0 51.0 84.7 32.9 98.8 35.3 NF NF S0104 20 1.19 20/160 20/200 0.05 0.12 237.4 77.7 440.1 88.7 63.0 30.9 64.6 30.1 NF NF S0110 26 1.02 20/200 20/125 0.65 0.56 333.8 94.5 349.4 98.7 68.9 32.1 68.9 32.5 R1129L NF S0049 34 2.13 20/50 20/200 0.76 0.92 374.4 97.2 344.0 90.5 81.0 32.9 65.8 33.7 R1129L NF S0075 22 1.06 20/63 20/125 0.40 0.69 454.5 114.0 452.7 122.8 77.5 32.1 75.5 32.9 G1961E NF S0039 36 2.2 20/160 20/100 0.15 0.13 347.7 137.1 395.8 142.0 80.1 31.3 61.7 30.9 M1V R2107H S0054 31 1.93 20/40 20/40 0.41 0.56 ND ND ND ND ND ND ND ND G1961E S2255I S0040 11 2.97 20/160 20/160 0.46 0.07 610.2 72.5 375.6 67.4 106.5 37.2 93.5 32.9 R572X N1805D S0028 54 2.73 20/16 20/16 1.04 1.54 425.5 105.8 386.3 107.8 83.4 34.4 84.1 34.8 L541P/A1038V R2030Q ND ¼ not done. Login to comment
81 ID# Age Years followed Visual Acuity AL Area (mm2 ) HF Area (mm2 ) ffERG Amplitudes (mV) ffERG IT (msec) ABCA4 Variants OD OS OD OS OD OS OD OS OD OS Rod Cone Rod Cone Rod Cone Rod Cone AI AII Group A S0047 53 2.83 20/40 20/40 31.60 33.85 0.20 0.07 304.0 125.4 392.9 143.3 69.5 29.3 72.7 29.3 NF NF S0023 49 3.26 20/160 20/160 9.92 12.67 1.24 1.49 292.1 52.2 272.4 46.4 77.9 36.8 78.3 35.2 L541P/A1038V NF S0050 78 2.71 20/250 20/160 2.02 0.07 1.21 0.67 355.0 82.2 373.1 87.2 76.7 34.1 76.7 34.8 S2255I IVS5,&#fe;1,G > C S0045 44 3.16 20/200 20/160 17.27 44.72 NM NM 177.0 55.7 201.9 50.0 85.3 41.5 87.7 39.9 L541P/A1038V R2107K S0018 35 2.28 20/200 20/250 4.31 2.53 NM NM ND ND ND ND ND ND ND ND G1961E S2255I S0033 63 2.35 20/800 20/400 15.51 12.09 1.30 0.22 168.2 53.0 180.9 45.4 96.3 38.0 101.0 38.4 R943Q IVS8,-9, T > C S0048 62 2.56 20/80 20/20 48.45 40.73 NM NM 119.7 69.5 213.9 54.6 71.2 35.6 80.6 35.2 R290Q K346T S0036 62 2.81 20/640 20/500 55.70 43.38 NM NM 174.8 41.1 158.1 50.8 106.6 38.5 102.3 35.2 R1129L Q234X S0029 62 2.81 20/40 20/80 57.62 61.25 NM NM 219.0 26.0 209.2 35.2 77.9 31.3 73.6 30.9 R2030Q NF S0024 43 3.20 20/25 20/25 4.91 3.91 4.18 1.48 98.2 23.7 148.0 36.2 84.0 33.2 85.5 33.6 NF NF S0078 35 1.17 20/100 20/125 5.64 5.39 0.70 0.83 230.1 106.7 187.6 108.8 71.2 34.1 64.6 34.1 IVS39-10,T > C NF S0032 64 2.56 20/250 20/320 8.67 3.67 0.67 0.74 273.2 75.5 235.1 114.7 87.9 30.5 72.7 30.1 R1108C L2027F S0051 52 1.90 20/25 20/20 32.78 29.23 NM NM ND ND ND ND ND ND ND ND E471K NF S0115 16 0.57 20/50 20/50 0.77 3.43 NM NM ND ND ND ND ND ND ND ND NF NF S0077 49 1.14 20/40 20/25 N/A 8.54 0.16 1.89 279.9 111.9 299.3 105.2 N/A N/A N/A N/A NF NF S0042 43 1.84 20/125 20/200 118.15 126.69 NM NM 122.3 27.7 114.8 29.3 85.7 36.4 89.6 36.0 S2255I E471K S0037 46 2.38 20/125 20/200 8.73 N/A 1.29 0.86 338.7 119.3 373.7 109.4 72.3 28.1 70.7 28.1 G1961E S2255I S0020 42 0.0 20/200 20/160 1.16 1.82 NM NM 140.4 43.2 159.9 45.8 81.3 31.3 71.5 29.3 NF NF S0041 44 0.0 20/200 20/160 4.73 7.09 0.96 1.36 260.5 65* 297.2 95.3 113.7 29.7 91.8 28.9 R1129L NF S0087 44 0.0 20/20 20/20 14.89 23.09 NM NM 180.9 66.8 182.2 78.0 76.1 32.9 72.2 32.9 IVS40, &#fe;5,G > A NF S0053 43 0.0 20/100 20/160 1.33 1.85 NM NM ND ND ND ND ND ND ND ND S2255I NF S0097 73 0.0 20/200 20/200 49.21 54.26 NM NM ND ND ND ND ND ND ND ND D1532E NF S0080 28 0.0 20/125 20/200 NA 0.98 0.56 0.03 333.1 117.2 325.1 121.4 80.2 32.5 82.6 32.9 E1122K S2255I S0210 49 0.0 20/160 20/200 0.21 NA NM NM 304.1 76.1 425.7 81.1 72.8 33.7 79.8 33.7 NF NF Group B S0133 30 0.0 20/125 20/32 0.51 0.01 387.1 123.7 374.8 105.1 65.4 32.9 65.0 32.9 NF NF S0046 49 0.0 20/160 20/160 1.48 1.68 491.2 148.9 494.9 145.3 72.7 30.1 77.3 29.7 P1380L G1961E S0141 40 0.0 20/13 20/32 1.88 0.41 389.0 156.5 343.5 150.6 70.8 33.3 69.7 34.4 NF NF S0058 61 0.0 20/50 20/50 1.48 1.52 ND ND ND ND ND ND ND ND NF NF S0149 16 0.0 20/80 20/100 1.59 0.62 285.0 87.4 333.4 115.3 62.6 32.5 61.4 32.5 NF NF S0083 15 0.0 20/13 20/13 0.17 0.48 441.1 144.2 472.0 155.5 74.4 33.3 71.6 33.3 G863A NF S0216 44 0.0 20/25 20/32 0.52 1.04 228.7 97.7 192.7 75.3 83.8 36.8 85.7 36.0 NF NF S0076 9 0.0 20/200 20/160 3.70 4.23 557.7 139.5 319.8 117.3 81.6 29.7 73.4 28.9 W1408R T1526M S0021 19 0.0 20/160 20/160 1.81 1.08 390.4 202.1 ND ND 63.3 29.3 ND ND L2027F W31R S0085 35 0.0 20/16 20/20 2.70 2.56 ND ND ND ND ND ND ND ND C54T R219T S0044 30 0.0 20/250 20/250 4.23 3.77 ND ND ND ND ND ND ND ND A1794D L2027F S0035 47 0.0 20/160 20/125 0.46 0.13 239.6 112.3 325.0 141.6 64.1 28.1 62.5 28.1 G863A E471K S0065 61 0.0 20/100 20/125 0.83 0.15 243.4 58.6 226.5 49.2 74.8 32.9 84.5 33.3 G1961E NF S0213 27 0.0 20/25 20/25 0.99 1.03 384.2 124.4 424.4 137.9 72.4 31.7 72.4 35.2 NF NF S0088 55 0.0 20/25 20/20 0.11 0.47 ND ND ND ND ND ND ND ND R1898H NF S0127 16 0.0 20/63 20/63 0.08 0.69 536.3 128.9 470.3 136.4 65.4 30.9 77.1 30.9 L541P/A1038V NF S0057 47 0.48 20/125 20/160 1.20 1.75 252.1 80.3 210.5 100.5 75.5 32.9 89.6 32.5 NF NF S0043 53 2.91 20/200 20/200 0.97 0.53 250.5 173.2 354.6 179.2 72.7 28.5 80.1 30.1 G1961E F873I S0101 37 1.1 20/40 20/20 0.14 0.25 382.2 159.7 422.7 156.7 70.5 32.5 74.0 32.9 A1038V IVS42 &#fe; 1,G > A S0027 17 2.18 20/50 20/50 1.60 2.12 196.3 36.3 198.0 51.0 84.7 32.9 98.8 35.3 NF NF S0104 20 1.19 20/160 20/200 0.05 0.12 237.4 77.7 440.1 88.7 63.0 30.9 64.6 30.1 NF NF S0110 26 1.02 20/200 20/125 0.65 0.56 333.8 94.5 349.4 98.7 68.9 32.1 68.9 32.5 R1129L NF S0049 34 2.13 20/50 20/200 0.76 0.92 374.4 97.2 344.0 90.5 81.0 32.9 65.8 33.7 R1129L NF S0075 22 1.06 20/63 20/125 0.40 0.69 454.5 114.0 452.7 122.8 77.5 32.1 75.5 32.9 G1961E NF S0039 36 2.2 20/160 20/100 0.15 0.13 347.7 137.1 395.8 142.0 80.1 31.3 61.7 30.9 M1V R2107H S0054 31 1.93 20/40 20/40 0.41 0.56 ND ND ND ND ND ND ND ND G1961E S2255I S0040 11 2.97 20/160 20/160 0.46 0.07 610.2 72.5 375.6 67.4 106.5 37.2 93.5 32.9 R572X N1805D S0028 54 2.73 20/16 20/16 1.04 1.54 425.5 105.8 386.3 107.8 83.4 34.4 84.1 34.8 L541P/A1038V R2030Q ND &#bc; not done. Login to comment

PMID: 19265867 [PubMed] Passerini I et al: "Novel mutations in of the ABCR gene in Italian patients with Stargardt disease."

No. Sentence Comment

57 Table 2 Summary of the mutations identified in the ABCR gene in our series of STGD Italian patients Patient Allele 1 mutation Allele 2 mutation S 1 R212C T1019M S 8 V1433I V1433I S 21 A1598D A1598D S 33 N96K G978D S 56 A1598D G1961E S 70 R212C T1019M S 71 W700X WT S 74 6750delA V767D S 77 G1961E WT S 82 Q21X G1961E S 106 C1177X G1961E S 107 C1177X G1961E S 114 T970P-F1015E - S 115 T970P-F1015E - S 120 N415K G1961E S 162 324-327insT 324-327insT S 181 W1408X G1961E S 190 C1177X A1598D S 201 G1961E WT S 202 Q21X T970P-F1015E S 213 M840R G1961E S 231 WT WT S 236 C1177X G1961E S 237 WT WT S 241 V256 splice WT S 246 IVS6-1g4t R1108C S 260 L2221P 5109delG-I156V S 321 IVS9 þ 1G4C S1099X S 328 IVS42 þ 4delG IVS35 þ 2t4c S 346 E2096K WT S 347 IVS28 þ 5g4a WT S 353 P1484S-G1961E P68L S 354 P1484S-G1961E P68L S 355 P1484S-G1961E P68L S 360 G1961E 5961delGGAC S 364 IVS35 þ 2t4c G1961E S 365 L541P/A1038V G1961E S 377 IVS42 þ 4delG IVS35 þ 2t4c S 380 R653C WT S 413 R212C T1019M S 414 A1598D G1961E S 417 G1078E G1961E S 438 R1055W WT S 440 4021ins24bp T1526M-G1961E S 449 W1479X L2140Q S 450 W1479X L2140Q S 474 W1461X G 1977S S 486 WT WT S 492 R1098C/L1970F 6548insTGAA S 528 T977P IVS40 þ 5g4a S 531 G690V Q1332X S 532 R572X L1473M-4733delGTTT S 535 IVS40 þ 5g4a 5917delG S 550 IVS40 þ 5g4a 6750delA S 555 250insCAAA WT S 556 250insCAAA WT S 575 N96H G1961E S 590 W821R IVS40 þ 5g4a S 592 V931M R1108C S 593 V767D R2030X Table 2 (Continued ) Patient Allele 1 mutation Allele 2 mutation S 594 G172S G1961E S 602 P1380L G1961E S 607 E616K L1580S-K2172R S 640 250insCAAA S1696N S 694 IVS35 þ 2t4c G1961E S 725 IVS13 þ 1g4a Q1376 splice S 731 L541P-A1038V G1961E S 755 N965S IVS40 þ 5g4a S 789 E1087K G1977S S 968 T1019M G1961E S 992 R212C G1961E Bold values indicate novel mutations. Login to comment
85 Therefore, it can be speculated that its clinical expression depends on the mutation severity on the fellow allele, as suggested by earlier genotype/ phenotype studies.17,21 Still, although the A1038V mutation is commonly reported in the literature,9,13,27 in our series, it was detected in only two patients (1.4% of the patients, 0.7% of the alleles) within the L541P-A1038V complex allele. Login to comment

PMID: 19578016 [PubMed] Genead MA et al: "The natural history of stargardt disease with specific sequence mutation in the ABCA4 gene."

No. Sentence Comment

66 Genetic Mutations in the ABCA4 Gene in the Patients Patient No. Genetic Mutation Allele 1 Genetic Mutation Allele 2 Comments 1 gly1961glu exon 42 Heterozygous 2 gly1961glu exon 42 ala1038val exon 21 and leu541pro exon 12 Compound heterozygous 3 gly1961glu exon 42 Heterozygous 4 gly1961glu exon 42 arg2077trp exon 45 Compound heterozygous 5 gly1961glu exon 42 gly65glu exon 3 Compound heterozygous 6 gly1961glu exon 42 leu1201arg exon 24 Compound heterozygous 7 gly1961glu exon 42 Heterozygous 8 gly1961glu exon 42 Heterozygous 9 gly1961glu exon 42 del Co 1620-1622 exon 35 Compound heterozygous 10 gly1961glu exon 42 Heterozygous 11 gly1961glu exon 42 1bp del(T) Co 36 which creates stop at Co 38 Compound heterozygous 12 gly1961glu exon 42 IVS38-10 TϾC Compound heterozygous 13 gly1961glu exon 42 Heterozygous 14 gly1961glu exon 42 pro1380leu Compound heterozygous 15 gly1961glu exon 42 pro1380leu Compound heterozygous 16 gly1961glu exon 42 gly1961glu exon 42 Homozygous initial visit in the right eye was 0.87 (range, 0.10-1.40), whereas the median logMAR VA at the most recent FU visit was 1.00 (range, 0.18-2.80; P ϭ 0.325). Login to comment

PMID: 19406377 [PubMed] Pasadhika S et al: "Peripapillary retinal nerve fiber layer thinning in patients with autosomal recessive cone-rod dystrophy."

No. Sentence Comment

60 Age (years) Gender Race Genetic Testing Results for the ABCA4 Gene Visual Acuity Fundus Findings Right Eye Left Eye Macula Pigmentation 1 60 Female White IVS40ϩ5 G¡A & cys54tyr exon 3, heterozygous 20/400 20/400 Pigment clumping Posterior pole, midperiphery 2 59 Female White glu328stop exon 8 & val767asp, heterozygous 3/200 3/400 Pigment clumping Posterior pole, midperiphery 3 44 Male White ala1038val exon 21 & leu541pro exon 12, heterozygousa 5/400 5/200 Pigment clumping Periphery 4 54 Female Black val989ala exon 20, heterozygous 20/400 CF Pigment clumping Posterior pole, peripapillary 5 42 Male Palestinian None detectedb 20/50 20/400 Drusen-like lesions, hypopigmentation - 6 45 Female Palestinian None detectedb 20/70 20/200 Drusen-like lesions, hypopigmentation - 7 63 Female Black None detectedb 20/200 20/200 Geographic atrophic lesions - 8 69 Female White No genetic testing 2/400 2/700 Pigment granularity - 9 62 Female White Pending 20/200 20/400 Bull`s-eye-like lesions - 10 16 Male White No genetic testing 10/300 10/200 Geographic atrophic lesions - 11 11 Male White No genetic testing 10/120 10/160 Bull`s-eye-like lesions and pigment granularity Few at midperiphery CF ϭ counting fingers. Login to comment
62 Age (years) Gender Race Genetic Testing Results for the ABCA4 Gene Visual Acuity Fundus Findings Right Eye Left Eye Macula Pigmentation 1 60 Female White IVS40af9;5 G&#a1;A & cys54tyr exon 3, heterozygous 20/400 20/400 Pigment clumping Posterior pole, midperiphery 2 59 Female White glu328stop exon 8 & val767asp, heterozygous 3/200 3/400 Pigment clumping Posterior pole, midperiphery 3 44 Male White ala1038val exon 21 & leu541pro exon 12, heterozygousa 5/400 5/200 Pigment clumping Periphery 4 54 Female Black val989ala exon 20, heterozygous 20/400 CF Pigment clumping Posterior pole, peripapillary 5 42 Male Palestinian None detectedb 20/50 20/400 Drusen-like lesions, hypopigmentation - 6 45 Female Palestinian None detectedb 20/70 20/200 Drusen-like lesions, hypopigmentation - 7 63 Female Black None detectedb 20/200 20/200 Geographic atrophic lesions - 8 69 Female White No genetic testing 2/400 2/700 Pigment granularity - 9 62 Female White Pending 20/200 20/400 Bull`s-eye-like lesions - 10 16 Male White No genetic testing 10/300 10/200 Geographic atrophic lesions - 11 11 Male White No genetic testing 10/120 10/160 Bull`s-eye-like lesions and pigment granularity Few at midperiphery CF afd; counting fingers. Login to comment

PMID: 19324865 [PubMed] Gomes NL et al: "A comparison of fundus autofluorescence and retinal structure in patients with Stargardt disease."

No. Sentence Comment

97 Summary of Genetic and Selected Clinical Findings Patient Age Sex Allele 1 Allele 2 Visual Acuity (LogMAR) PRL (Degrees) PRL Location OD OS OD OS OD OS 1 12 M K346T ND 0.7 0.7 5.8 5.9 S S 2 42 M ND ND 1.0 1.0 1.9 2.0 S S 3 31 M G1961E G1961E 0.5 0.5 2.8 1.9 S S 4 56 M P1380L S1696N 0.7 0.7 8.4 8.0 S S 5 23 F L541P/A1038V G1961E 1.0 1.0 0.0 0.0 F F 6 62 F D1532N G1961E 1.3 0.4 3.0 0.0 T F 7 65 F G1961E ND 0.3 1.3 4.0 2.0 S S 8 30 F G1961E ND 0.4 0.4 2.9 3.0 S S 9 24 F P1380L P1380L 0.3 0.3 8.6 8.5 S S 10 15 F L541P/A1038V G1961E 0.0 0.0 0.0 0.0 F F 11 20 F L541P/A1038V ND 0.3 0.4 1.8 2.0 S S ND, not determined; S, superior; F, foveal; T, temporal. Login to comment

PMID: 19230850 [PubMed] Molday RS et al: "The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration."

No. Sentence Comment

257 Some mutations affect only the retinal activated ATPase activity such as the G1975D and K1978M mutations in NBD2, whereas a large number of mutants affect both the basal and retinal stimulated ATPase activity of ABCA4 as exemplified by the L541P mutation in ECD1, T971N in NBD1 and E2096K in NBD2 [35]. Login to comment

PMID: 19217903 [PubMed] Cella W et al: "G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy."

No. Sentence Comment

89 Of the compound heterozygous group, 5 patients from 2 families had the complex mutation L541P/A1038V, 2 patients (siblings) had the splicing mutation IVS20 þ 5G / A, and 5 patients had missense mutations Q636H, R2077W, T1253M, C54Y and D1532N (Table 1). Login to comment
122 Five patients from 2 unrelated families carried the complex mutation L541P/A1038V in addition to the G1961E allele. Login to comment
142 Case #, sex Age of onset Duration (years) Visual acuity (OD, OS) Allele 2 Bull`s eye type (FAF) SD-OCT MP-1 1, f 20 1 20/25, 20/40 G1961E (homozygous) B Not tested Not tested 2, f 49 13 20/200, 20/150 G1961E (homozygous) B Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 4 degrees OD and in the central 6 degrees OS, eccentric PRL (superior retina) 3, m 19 13 20/70, 20/70 G1961E (homozygous) A Not tested Absolute scotoma in the central 6 degrees in both eyes, eccentric PRL (superior retina) 4.1, f 17 30 20/200, 20/200 L541P/A1038V B Not tested Not tested 4.2, m 28 2 20/25, 20/30 L541P/A1038V B Not tested Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 4.3, m 28 2 20/30, 20/40 L541P/A1038V B Not tested Decreased sensitivity by 9 dB OD and 11 dB OS in the central 2 degrees, foveal fixation 5.1, f 14 5 20/200, 20/400 L541P/A1038V C Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Decreased sensitivity by 8 dB in the central 2 degrees in both eyes, eccentric PRL (superior retina) 5.2, f 14 1 20/20, 20/25 L541P/A1038V A Photoreceptor disorganization, normal ONL and normal RPE Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 6.1, f 17 5 20/100, 20/100 IVS20 þ 5G / A C Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 2 degrees in both eyes, eccentric PRL (superior retina) 6.2, m 14 3 20/40, 20/25 IVS20 þ 5G / A A Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Absolute scotoma in the central 2 degrees OD and decreased sensitivity by 18 dB in the central 2 degrees OS, eccentric PRL (superior retina) 7, m 28 12 20/200, 20/150 Q636H B Photoreceptor loss, thinner ONL and RPE atrophy Not tested 8, f 25 9 20/80, 20/25 R2077W B Not tested Not tested 9, m 67 2 20/800, 20/60 T1253M B Not tested Not tested 10, f 26 10 20/80, 20/80 C54Y B Not tested Not tested 11, f 44 20 20/400, 20/60 D1532N C Not tested Absolute scotoma in the central 8-10 degrees OD and absolute scotoma in the central 8 degrees OS, eccentric PRL (superior retina) Abbreviations: m, male; f, female; OD, right eye; OS, left eye; FAF, fundus autofluorescence; bull`s eye type A, presence of a ring of increase autofluorescence surrounding decreased autofluorescence; bull`s eye type B, decreased fovea autofluorescence without a surrounding ring of increase autofluorescence; bull`s eye type C, speckled macular appearance with slightly increased surround autofluorescence; SD-OCT, spectral-domain optical coherence tomography; ONL, outer nuclear layer; MP-1, microperimetry; and PRL, preferred retinal location. Login to comment
164 In the compound heterozygous group, 5 patients had the complex mutation allele L541P/A1038V, in addition to G1961E. Login to comment
168 The L541P/A1038V mutation has been described in patients with more favorable clinical prognosis (Hargitai et al., 2005). Login to comment
169 Similarly, although G1961E is considered a ''mild- to-moderate`` allele, it has been reported in bull`s eye maculopathy with more severe phenotype such as extensive atrophic RPE changes (Gerth et al., 2002; Simonelli et al., 2005). Login to comment
143 Case #, sex Age of onset Duration (years) Visual acuity (OD, OS) Allele 2 Bull`s eye type (FAF) SD-OCT MP-1 1, f 20 1 20/25, 20/40 G1961E (homozygous) B Not tested Not tested 2, f 49 13 20/200, 20/150 G1961E (homozygous) B Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 4 degrees OD and in the central 6 degrees OS, eccentric PRL (superior retina) 3, m 19 13 20/70, 20/70 G1961E (homozygous) A Not tested Absolute scotoma in the central 6 degrees in both eyes, eccentric PRL (superior retina) 4.1, f 17 30 20/200, 20/200 L541P/A1038V B Not tested Not tested 4.2, m 28 2 20/25, 20/30 L541P/A1038V B Not tested Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 4.3, m 28 2 20/30, 20/40 L541P/A1038V B Not tested Decreased sensitivity by 9 dB OD and 11 dB OS in the central 2 degrees, foveal fixation 5.1, f 14 5 20/200, 20/400 L541P/A1038V C Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Decreased sensitivity by 8 dB in the central 2 degrees in both eyes, eccentric PRL (superior retina) 5.2, f 14 1 20/20, 20/25 L541P/A1038V A Photoreceptor disorganization, normal ONL and normal RPE Decreased sensitivity by 6 dB in the central 2 degrees in both eyes, foveal fixation 6.1, f 17 5 20/100, 20/100 IVS20 &#fe; 5G / A C Photoreceptor loss, thinner ONL and RPE atrophy Absolute scotoma in the central 2 degrees in both eyes, eccentric PRL (superior retina) 6.2, m 14 3 20/40, 20/25 IVS20 &#fe; 5G / A A Photoreceptor loss (foveal optical gap), thinner ONL and normal RPE Absolute scotoma in the central 2 degrees OD and decreased sensitivity by 18 dB in the central 2 degrees OS, eccentric PRL (superior retina) 7, m 28 12 20/200, 20/150 Q636H B Photoreceptor loss, thinner ONL and RPE atrophy Not tested 8, f 25 9 20/80, 20/25 R2077W B Not tested Not tested 9, m 67 2 20/800, 20/60 T1253M B Not tested Not tested 10, f 26 10 20/80, 20/80 C54Y B Not tested Not tested 11, f 44 20 20/400, 20/60 D1532N C Not tested Absolute scotoma in the central 8-10 degrees OD and absolute scotoma in the central 8 degrees OS, eccentric PRL (superior retina) Abbreviations: m, male; f, female; OD, right eye; OS, left eye; FAF, fundus autofluorescence; bull`s eye type A, presence of a ring of increase autofluorescence surrounding decreased autofluorescence; bull`s eye type B, decreased fovea autofluorescence without a surrounding ring of increase autofluorescence; bull`s eye type C, speckled macular appearance with slightly increased surround autofluorescence; SD-OCT, spectral-domain optical coherence tomography; ONL, outer nuclear layer; MP-1, microperimetry; and PRL, preferred retinal location. Login to comment
165 In the compound heterozygous group, 5 patients had the complex mutation allele L541P/A1038V, in addition to G1961E. Login to comment

PMID: 19243736 [PubMed] Kellner S et al: "Lipofuscin- and melanin-related fundus autofluorescence in patients with ABCA4-associated retinal dystrophies."

No. Sentence Comment

32 Age Gender ABCA4 Mutation VA RE/LE Full-field ERG Multifocal ERG Group 1a CRD 2808 34 F c.5413AϾG (p.Asn1805Asp) c.4880_4903dup24 (p.Leu1627_Ala1634dup) 0.05 0.05 DA and LA markedly reduced No recordable potentials CRD 2830 53 F c.2690CϾT (p.Thr897Ile), c.6176GϾC (p.Gly2059Ala) 0.5 0.7 DA and LA moderately reduced Pericentral amplitude reduction CRD 2797 54 M c.4297GϾA (p.Val1433Ile) 2. mutation not foundc 0.1 0.16 DA and LA moderately reduced Not done SD 2872 44 F c.4462TϾC (p.Cys1488Arg) 2. mutation not done 0.6 0.7 DA and LA borderline Central amplitude reduction CRD 2861 72 F c.122GϾA (p.Trp41Ter) 2. mutation not done 0.4 0.5 DA: mildly and LA: moderately reduced Central amplitude reduction CRD 2644 67 F c.634CϾT (p.Arg212Cys), c.656GϾC (p.Arg219Thr), c.2588GϾC (p.Gly863Ala/ delGly863) 0.6 0.04 DA and LA moderately reduced Central amplitude reduction CRD 2936 44 F c.1622TϾC (p.Leu541Pro)/ c.3113CϾT (p.Ala1038Val), 2. mutation not done 1.0 1.0 DA: mildly and LA: moderately reduced Pericentral amplitude reduction Group 2b SD 2837 42 M c.1622TϾC (p.Leu541Pro)/ c.3113CϾT (p.Ala1038Val), c.5882GϾA (p.Gly1961Glu) 0.16 0.16 Normal Central amplitude reduction SD 2780 37 M c.768GϾT (splice mutation) c.5882GϾA (p.Gly1961Glu) 0.1 0.1 Normal Central amplitude reduction SD 2942 47 F c.1622TϾC (p.Leu541Pro) c.6320 GϾA (p.Arg2107His) 0.1 0.16 Not done Central amplitude reduction SD 2930 40 F c.6089G?e;A (p.Arg2030Gln) c.6543del36bp, (p.Leu2182_Phe2193del) 0.1 0.1 DA and LA mildly reduced Central amplitude reduction SD 2933 43 F c.1609CϾT (p.Arg537Cys) c.5882GϾA (p.Gly1961Glu) c.1654GϾA (p.Val552Ile) 0.05 0.1 Normal Not done SD 2669 13 F c.768GϾT (splice mutation) c.6449GϾA (p.Cys2150Tyr) 0.1 0.16 DA and LA borderline Central amplitude reduction SD 2700 22 F c.1609CϾT (p.Arg537Cys) c.2588GϾC (p.Gly863Ala) 0.1 0.1 Normal Central amplitude reduction SD 2833 29 M c.1928TϾG (p.Val643Gly) 2. mutation not foundc 0.1 0.1 Normal Not done SD 2799 13 M c.3113CϾT (p.Ala1038Val) c.5461-10TϾC 0.4 0.4 Not done Central amplitude reduction CRD ϭ cone-rod dystrophy; DA ϭ dark adaptation; ERG ϭ electroretinography; F ϭ female; LA ϭ light adaptation; LE ϭ left eye; M ϭ male; RE ϭ right eye; SD ϭ Stargardt disease; VA ϭ visual acuity. Login to comment

PMID: 18285826 [PubMed] Kitiratschky VB et al: "ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies."

No. Sentence Comment

70 of alleles Reference Missense: 6 c.731T4Ca p.L244P 2 23 12 c.1622T4Cb p.L541P 1 5 13 c.1928T4G p.V643G 1 9 17 c.2588G4C p.G863A and p.G863del 2 4 21 c.3113C4Tb p.A1038V 1 4 25 c.3608G4A p.G1203E 1 24 28 c.4139C4T p.P1380L 2 25 30 c.4457C4T p.P1486L 1 25 30 c.4462T4C p.C1488R 1 25 37 c.5285C4A p.A1762D 1 24 41 c.5819T4C p.L1940P 1 26 42 c.5882G4A p.G1961E 1 9 45 c.6148G4C p.V2050L 1 25 45 c.6229C4T p.R2077W 1 25 Nonsense: 6 c.700C4T p.Q234X 1 This study 6 c.735T4G p.Y245X 2 24 28 c.4234C4T p.Q1412X 1 10 Deletion: 24 c.3539_3554del p.S1181PfsX8 1 This study 43 c.5917delG p.V1973X 3 27 Splice site/intronic: 26 c.5196+1G4A Splicing 1 9 34 c.4848+2T4C Splicing 1 This study 36 c.5196+1_5196+4del Splicing 1 15 39 c.5461À10T4C Unknown 8 14 40 c.5714+5G4A Splicing? Login to comment

PMID: 16644365 [PubMed] Michaelides M et al: "Progressive cone and cone-rod dystrophies: phenotypes and underlying molecular genetic basis."

No. Sentence Comment

245 It is currently believed that homozygous null mutations cause the most severe phenotype of autosomal recessive retinitis pigmentosa (RP), combinations of a null mutation with a moderate missense mutation result in autosomal recessive CORD, and combinations of null/mild missense or two moderate missense mutations cause STGD/FFM (Fundus Flavimaculatus).197 Assessment of functional activity of mutant ABCA4 transporter has been performed by Sun et al.190 For example, the missense mutations, Leu541Pro and Gly1961Glu, are associated with severely reduced but not abolished ATPase activity, whereas nonsense mutations would be predicted to have a more severe effect on protein function. Login to comment

PMID: 16303926 [PubMed] Hargitai J et al: "Correlation of clinical and genetic findings in Hungarian patients with Stargardt disease."

No. Sentence Comment

11 The most frequent ABCA4 alleles in Hungarian patients with STGD were L541P/A1038V (in 28% of all patients), G1961E (20%) and IVS40ϩ5G3A (17%). Login to comment
82 The most frequent ABCA4 allele in the Hungarian STGD population was the complex allele L541P/A1038V at 14.3% (i.e., 28% of all screened patients carried at least one allele). Login to comment
89 Summarized Clinical and Genetic Data of Patients with STGD Patient Allele 1 Allele 2 Fishman OU Gender Age Duration VA OD VA OS FT OD (␮m) FT OS (␮m) MV OD (mm3 ) MV OS (mm3 ) 1 ND ND I M 18 10 0.42 0.50 90.00 76.00 1.70 1.67 2 L541P/A1038V ND III F 27 15 0.06 0.08 43.00 58.00 1.27 1.28 3 5917delG 5917delG II F 29 8 0.17 0.17 54.00 20.00 1.38 1.35 4 ND ND III F 42 14 0.10 0.10 91.00 71.00 1.60 1.59 5 V2050L ND II F 22 5 0.20 0.33 28.00 77.00 1.64 1.68 6 ND ND II F 17 2 1.00 0.71 156.00 141.00 2.55 2.6 7 IVS40ϩ5GϾA ND III M 28 13 0.10 0.06 71.00 92.00 1.61 1.61 8 L541P/A1038V G1961E II M 37 15 0.10 0.10 87.00 97.00 1.95 1.95 9 106delT G1961E II M 32 7 0.08 0.08 51.00 32.00 1.59 1.66 10 ND ND I F 55 17 0.25 0.56 160.00 170.00 1.72 1.82 11 L541P/A1038V G863A II F 15 3 0.25 0.33 67.00 68.00 1.78 1.76 12 IVS40ϩ5GϾA 5917delG III M 15 6 0.20 0.20 107.00 117.00 1.93 1.92 13 ND ND I M 27 2 0.38 0.33 56.00 86.00 2.01 1.97 14 G1886E G1961E II F 37 9 0.12 0.16 92.00 46.00 1.55 1.59 15 G1961E ND III F 20 5 0.30 0.20 49.00 34.00 1.43 1.53 16 ND ND II M 28 14 0.32 0.08 52.00 60.00 1.46 1.52 17 IVS40ϩ5GϾA 5917delG III M 27 5 0.10 0.10 97.00 92.00 1.76 1.71 18 L541P/A1038V D1532N III M 28 12 0.25 0.10 49.00 46.00 1.83 1.86 19 ND ND II F 31 11 0.10 0.13 67.00 72.00 1.55 1.49 20 L541P L541P/A1038V II F 15 5 0.10 0.10 28.00 34.00 1.63 1.65 21 L541P/A1038V G863A II F 25 2 0.20 0.62 94.00 81.00 1.92 1.94 22 L541P/A1038V ND II M 18 9 0.08 0.10 63.00 72.00 1.40 1.43 23 G1961E ND III F 34 9 0.16 0.16 16.00 23.00 1.31 1.56 24 ND ND II F 52 14 0.16 0.16 122.00 113.00 1.90 1.99 25 P68L L541P/A1038V III M 37 22 0.10 0.12 40.00 40.00 1.41 1.42 26 ND ND II F 18 11 0.20 0.25 59.00 72.00 1.42 1.47 27 L541P/A1038V G1961E II F 24 7 0.18 0.18 83.00 100.00 1.72 1.77 28 IVS40ϩ5GϾA 5917delG III M 15 7 0.10 0.16 38.00 46.00 1.30 1.41 29 R1108C R1108C II M 31 14 0.10 0.10 41.00 44.00 1.95 1.96 30 G1961E ND II M 28 6 0.33 0.56 91.00 129.00 1.98 2.04 31 ND ND II F 28 11 0.08 0.10 55.00 63.00 1.52 1.59 32 L541P/A1038V G863A II M 32 15 0.20 0.20 92.00 86.00 1.80 1.75 33 ND ND II F 27 4 0.25 0.20 66.00 75.00 1.72 1.76 34 ND ND II F 36 8 0.12 0.10 58.00 69.00 1.59 1.56 35 IVS40ϩ5GϾA IVS40ϩ5GϾA III F 19 6 0.10 0.10 62.00 53.00 1.67 1.65 Fishman OU, classification of patients by fundus photos in three categories according to Fishman et al.25 ND, not determined. Login to comment
94 However, when coupled with a deleterious variant such as the 5917delG mutation, it seems to result in a more severe phenotype.21 Patients with the L541P/A1038V complex allele were classified as phenotype II in 70% (7/10) of cases, the rest (3/10) as belonging to the phenotype III group (Table 1). Login to comment
97 In patients compound heterozygous for the L541P/ A1038V and G863A alleles (patients 11, 21, 32), a decrease in vision with the duration of the disease was observed. Login to comment
131 First, patients with the G1961E mutation, although classified in phenotype groups II and III, show the slowest progression of the TMV loss. Login to comment
132 Therefore, patients with STGD with the G1961E variant have, in general, a better than average disease prognosis. Login to comment
133 This observation is supported by two earlier re- ports20,25 and could be explained by the fact that although the G1961E variant had a drastic effect on ATPase activity, it was comparable to the wild-type protein in yield.8 Second, patients with the L541P/A1038V complex allele have, near the average in all patients with STGD, a moderate rate of disease progression. Login to comment
134 In in vitro studies, the L541P/ A1038V variant demonstrated a reduced, but not completely abolished, ATPase activity.20 The subgroup of patients, compound heterozygous for the L541P/A1038V and G863A alleles, show a better prognosis (i.e., a slower progression of the disease). Login to comment
80 The most frequent ABCA4 allele in the Hungarian STGD population was the complex allele L541P/A1038V at 14.3% (i.e., 28% of all screened patients carried at least one allele). Login to comment
87 Summarized Clinical and Genetic Data of Patients with STGD Patient Allele 1 Allele 2 Fishman OU Gender Age Duration VA OD VA OS FT OD (òe;m) FT OS (òe;m) MV OD (mm3 ) MV OS (mm3 ) 1 ND ND I M 18 10 0.42 0.50 90.00 76.00 1.70 1.67 2 L541P/A1038V ND III F 27 15 0.06 0.08 43.00 58.00 1.27 1.28 3 5917delG 5917delG II F 29 8 0.17 0.17 54.00 20.00 1.38 1.35 4 ND ND III F 42 14 0.10 0.10 91.00 71.00 1.60 1.59 5 V2050L ND II F 22 5 0.20 0.33 28.00 77.00 1.64 1.68 6 ND ND II F 17 2 1.00 0.71 156.00 141.00 2.55 2.6 7 IVS40af9;5Gb0e;A ND III M 28 13 0.10 0.06 71.00 92.00 1.61 1.61 8 L541P/A1038V G1961E II M 37 15 0.10 0.10 87.00 97.00 1.95 1.95 9 106delT G1961E II M 32 7 0.08 0.08 51.00 32.00 1.59 1.66 10 ND ND I F 55 17 0.25 0.56 160.00 170.00 1.72 1.82 11 L541P/A1038V G863A II F 15 3 0.25 0.33 67.00 68.00 1.78 1.76 12 IVS40af9;5Gb0e;A 5917delG III M 15 6 0.20 0.20 107.00 117.00 1.93 1.92 13 ND ND I M 27 2 0.38 0.33 56.00 86.00 2.01 1.97 14 G1886E G1961E II F 37 9 0.12 0.16 92.00 46.00 1.55 1.59 15 G1961E ND III F 20 5 0.30 0.20 49.00 34.00 1.43 1.53 16 ND ND II M 28 14 0.32 0.08 52.00 60.00 1.46 1.52 17 IVS40af9;5Gb0e;A 5917delG III M 27 5 0.10 0.10 97.00 92.00 1.76 1.71 18 L541P/A1038V D1532N III M 28 12 0.25 0.10 49.00 46.00 1.83 1.86 19 ND ND II F 31 11 0.10 0.13 67.00 72.00 1.55 1.49 20 L541P L541P/A1038V II F 15 5 0.10 0.10 28.00 34.00 1.63 1.65 21 L541P/A1038V G863A II F 25 2 0.20 0.62 94.00 81.00 1.92 1.94 22 L541P/A1038V ND II M 18 9 0.08 0.10 63.00 72.00 1.40 1.43 23 G1961E ND III F 34 9 0.16 0.16 16.00 23.00 1.31 1.56 24 ND ND II F 52 14 0.16 0.16 122.00 113.00 1.90 1.99 25 P68L L541P/A1038V III M 37 22 0.10 0.12 40.00 40.00 1.41 1.42 26 ND ND II F 18 11 0.20 0.25 59.00 72.00 1.42 1.47 27 L541P/A1038V G1961E II F 24 7 0.18 0.18 83.00 100.00 1.72 1.77 28 IVS40af9;5Gb0e;A 5917delG III M 15 7 0.10 0.16 38.00 46.00 1.30 1.41 29 R1108C R1108C II M 31 14 0.10 0.10 41.00 44.00 1.95 1.96 30 G1961E ND II M 28 6 0.33 0.56 91.00 129.00 1.98 2.04 31 ND ND II F 28 11 0.08 0.10 55.00 63.00 1.52 1.59 32 L541P/A1038V G863A II M 32 15 0.20 0.20 92.00 86.00 1.80 1.75 33 ND ND II F 27 4 0.25 0.20 66.00 75.00 1.72 1.76 34 ND ND II F 36 8 0.12 0.10 58.00 69.00 1.59 1.56 35 IVS40af9;5Gb0e;A IVS40af9;5Gb0e;A III F 19 6 0.10 0.10 62.00 53.00 1.67 1.65 Fishman OU, classification of patients by fundus photos in three categories according to Fishman et al.25 ND, not determined. Login to comment
92 However, when coupled with a deleterious variant such as the 5917delG mutation, it seems to result in a more severe phenotype.21 Patients with the L541P/A1038V complex allele were classified as phenotype II in 70% (7/10) of cases, the rest (3/10) as belonging to the phenotype III group (Table 1). Login to comment
95 In patients compound heterozygous for the L541P/ A1038V and G863A alleles (patients 11, 21, 32), a decrease in vision with the duration of the disease was observed. Login to comment

PMID: 16103129 [PubMed] Wiszniewski W et al: "ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies."

No. Sentence Comment

2 We analyzed a cohort of 29 arRP families for the mutations in ABCA4 with a commercial microarray, ABCR-400 in addition to direct sequencing and segregation analysis, and identified both mutant alleles in two families (7%): compound heterozygosity for missense (R602W) and nonsense (R408X) alleles and homozygosity for a complex [L541P; A1038V] allele. Login to comment
26 Functional studies of missense alleles [L541P; A1038V], R602W and C1490Y in transgenic frogs demonstrate that they do not translocate to rod OSs (ROSs). Login to comment
33 The sequence analysis of ABCA4 in patients AR197-05 and AR197-06 revealed homozygosity for the complex ABCA4 allele [L541P; A1038V]. Login to comment
44 A WT 168-05 24 20/25 OD; 20/30 OS;VF , 308 OU RP N/A N/A 168-06 26 N/A RP N/A N/A AR192 192-03 9 20/20 OD; 20/25 OS;VF , 58 OU RP D2177N WT 192-04 19 20/30 OD; 20/40 OS;VF , 58 OU RP WT WT 192-05 19 20/30 OD; 20/40 OS;VF , 58 OU RP WT WT AR194 194-03 30 N/A RP D2177N WT 194-05 Childhood 20/25 OD; 20/40 OS RP N/A N/A 194-06 5 N/A RP D2177N WT 194-07 4 or 5 20/80 OU RP N/A N/A AR197 197-05 7 CF 3 feet OD; CF 2 feet OS RP [L541P; A1038V] [L541P; A1038V] 197-06 9 CF 5 feet OD; HM OS RP [L541P; A1038V] [L541P; A1038V] AR554 554-03 2 10/12 20/60 OU RP V2050L WT 554-04 1 9/12 N/A RP N/A N/A AR591 591-03 20 20/25 OU RP N/A N/A 591-04 8 20/20 OD; 20/25 OS;VF , 108 OU RP G1961E WT AR689 689-03 7 N/A RP R408X R602W 689-08 7 N/A RP N/A N/A OD, right eye; OS, left eye; OU, both eyes; VF, visual field; RP, retinitis pigementosa, WT, wild type; N/A, not available; CF, counting fingers; HM, hand motions. Login to comment
80 (C-L) Microphotographs of 2-week-old X. laevis tadpoles expressing R602W (C and D), [L541P; A1038V] (E and F), L541P (G and H), A1038V (I and J) and C1490Y (K and L). Login to comment
82 Misfolded proteins are homogenously distributed in the inner segments and cell bodies, although the presence of fine aggregates was noted for L541P. Login to comment
92 Functional studies of the arRP-associated complex allele [L541P; A1038V] also showed abnormal localization to rod IS although the IF studies revealed a different staining pattern than R602W, because the mutant protein forms fine aggregates in the IS (Fig. 2E and F). Login to comment
93 The aggregate formation suggests a mechanism distinct from that observed for R602W may be responsible for the retention of [L541P; A1038V] in the IS. Login to comment
94 To determine which mutation prevents translocation of [L541P; A1038V] to ROS, we examined functionally the L541P and A1038V mutants independently. Login to comment
95 We observed retention of L541P in the IS (Fig. 2G and H) and correct localization of A1038V to ROS (Fig. 2I and J). Login to comment
96 These results suggest that L541P is a disease-causing mutation that affects ABCA4 processing. Login to comment
104 We employed this assay to examine the effects of [L541P; A1038V], R602W and C1490Y mutations on in vitro ATP hydrolysis. Login to comment
107 The rate of ATP hydrolysis of the complex allele [L541P; A1038V] was decreased to 68.1% of wild-type ABCA4 (Fig. 3). Login to comment
112 Decreased ATPase activity does not likely contribute to the overall pathogenicity of [L541P; A1038V] because localization to the ROS is the primary event that determines placement of the protein in its natural environment and is presumably required for it to perform its physiological function. Login to comment
113 Mutations: R602W, [L541P; A1038V] and C1490Y are frequently detected in patients with retinal diseases Mislocalization mutations R602W, [L541P; A1038V] and C1490Y have been reported as disease-associated mutations in patients with RP, CRD and STGD (18,20,32,33). Login to comment
119 WT and mutant constructs [L541P; A1038V], R602W and C1490Y ABCA4 were expressed in COS7 cells. Login to comment
136 Co-segregating compound heterozygous mutant alleles (R602W/R408X) and a homozygous complex allele [L541P; A1038V] were identified in two (AR689 and AR197) arRP families (Table 1). Login to comment
138 To examine this hypothesis, we generated transgenic X. laevis tadpoles expressing WT, [L541P; A1038V], R602W and C1490Y mutants and documented that the three mutant alleles cause mislocalization of ABCA4. Login to comment
146 Genotype-phenotype correlations among patients bearing one and two mislocalization-mutations Two mislocalization-alleles One mislocalization-allele RP STGD Allele 1 Allele 2 AO Allele 1 Allele 2 AO [L541P; A1038V] [L541P; A1038V] 7 [L541P; A1038V] L2027F 13 [L541P; A1038V] [L541P; A1038V] 9 [L541P; A1038V] R1108H 13 [L541P; A1038V] G1961E 16 CRD [L541P; A1038V] G1961E 28 Allele 1 Allele 2 AO [L541P; A1038V] L2027F 13 [L541P; A1038V] [L541P; A1038V] 10 [L541P; A1038V] L2027F 12 [L541P; A1038V] C1490Y 12 [L541P; A1038V] P1380L 5 R602W R602W 7 [L541P; A1038V] T1019M 6 [L541P; A1038V] G1961E 7 STGD [L541P; A1038V] T1019M 6 Allele 1 Allele 2 AO R602W L2027F 9 [L541P; A1038V] [L541P; A1038V] 12 C1490Y G1961E 28 C1490Y C1490Y 7 C1490Y G1961E 13 C1490Y R602W 9 C1490Y L2027F 10 C1490Y R602W 10 C1490Y L2027F 18 C1490 L2027F 18 AO-age of onset (in years). Login to comment
150 The results of IF studies of rods expressing [L541P; A1038V], R602W and C1490Y mutants were quite distinct from those observed for WT and ABCA4 EGFP. Login to comment
152 We also identified that L541P is responsible for the retention of the complex allele [L541P; A1038V], whereas A1038V seems to have no effect on ABCA4 processing. Login to comment
165 Presumed folding mutations, especially [L541P; A1038V] and C1490Y, have been frequently detected in patients with autosomal recessive macular degenerations (18,20,32,33). Login to comment
179 Shown is a proposed topological model of ABCA4 with its membrane spanning domains and the mutations: L541P, R602W, A1038V and C1490 analyzed. Login to comment
199 To generate the retinal dystrophy associated ABCA4 alleles: [L541P; A1038V], L541P, A1038V, R602W and C1490Y ABCA4, the pXOP-ABCA4 plasmid was mutagenized with Quickchange PCR-based mutagenesis system (Biocrest, La Jolla, CA, USA). Login to comment
228 In particular, we searched for subjects with RP, CRD and STGD in whom two mislocalization-mutant alleles [L541P; A1038V], R602W and C1490Y] were detected. Login to comment

PMID: 15696369 [PubMed] Yatsenko AN et al: "Evolution of ABCA4 proteins in vertebrates."

No. Sentence Comment

130 As anticipated, the most frequently occurring STGD- associated missense ABCA4 alterations (R212C, L541P, D645N, G863A, A1038V, R1108C, R1380L, W1408R, T1526M, R1640W, G1961E, L2027F, and L2030Q) map to highly conserved regions. Login to comment

PMID: 15494742 [PubMed] Klevering BJ et al: "Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa."

No. Sentence Comment

54 Although the segregation of the L541P and A1038 V mutations could not be tested in the respective families, we have grouped them as complex alleles, based on previous observations that these alterations invariably occur in cis configuration in German patients with CRD (Table 1).5,34 Indeed, all four patients carrying these variants (14488, 14752, 16242, and 16582) were from Germany. Login to comment
57 Table 1 ABCA4 sequence variants in CRD patients CRD patient number Inheritance Allele 1 Allele 2 Mutations segregateNucleotide change Effect Nucleotide change Effect 12608 Isolated IVS38-10T4C Unknowna IVS38-10T4C Unknowna Yes 14488 Isolated 1622T4C; 3113C4T L541P; A1038V Not identified NA 14750 Isolated 4918C4T R1640W Not identified NA 14752 Isolated 1622T4C; 3113C4T L541P; A1038V IVS38-10T4C Unknowna ? Login to comment
59 15428 Isolated 1622T4C; 3113C4T L541P; A1038V 2300T4A V767D ? Login to comment
62 16242 Isolated 1622T4C; 3113C4T L541P; A1038V Not identified NA 16243 Isolated 5381C4A A1794D 1789C4T P597S ? Login to comment
63 481G4A E161K 16569 Aut. rec. 3259G4A E1087K Not identified NA 16582 Isolated 1622T4C; 3113C4T L541P; A1038V IVS38-10T4C Unknowna ? Login to comment
101 Likewise, the known Table 2 ABCA4 sequence variants in RP patients RP patient number Inheritance Allele 1 Allele 2 Nucleotide change Effect Nucleotide change Effect 9304 Aut. Rec. 2588G4C; 2828G4Aa DG863/G863A; R943Q 5888delG R1963fs 9444 Aut. Rec. 6529G4A D2177N Not identified 9545 Isolated 6529G4A D2177N Not identified 14753 Isolated 1622T4C; 3113C4T L541P; A1038V Not identified 17597 Isolated 6148G4C V2050L Not identified a Polymorphic variants 4203A, 5603 T, and 5682C also present. Login to comment
143 Given this clinical presentation and the fact that homozygous null mutations were not found Table 5 Functional assessment of missense (A) and splice site (B) mutations (A) Missense mutation Nature of amino-acid change Effect on ABCR functionRef R18W Nonconservative Unknown R24C Nonconservative Unknown; adjacent to first transmembrane domain G65E Nonconservative Unknown E161K Nonconservative Unknown L541P Conservative Decreased ATP binding and ATPase activity50 P597S Nonconservative Unknown G618E Nonconservative Unknown V767D Nonconservative Decreased ABCR expression10 G863A Nonconservative Decreased ATPase activity50, 51 R943Q Nonconservative Decreased ATPase activity51 A1038V Conservative Decreased ATP binding and ATPase activity50 E1087K Nonconservative Decreased ATP binding50 V1433I Conservative Unknown R1640W Nonconservative Unknown A1794D Nonconservative Introduction charged aa in 10th transmembrane domain G1961E Nonconservative Decreased ATP binding and ATPase activity 50 V2050L Conservative Unknown D2177N Nonconservative Increased ATPase activity50 (B) Splice site mutation Effect on mRNARef Predicted effect on ABCR protein 768G4T Nonsense-mediated decay33 No protein IVS36+2T4C Unknown Truncation of exon 36 resulting in V1673fs? Login to comment

PMID: 15192030 [PubMed] Stenirri S et al: "Denaturing HPLC profiling of the ABCA4 gene for reliable detection of allelic variations."

No. Sentence Comment

35 Exon Genotypesa Exon Genotypesa 1b M1V (1A>G) (11) 24 3523-28TϾC (12) R18W (52C>T) (11) 25 G1203D (3608G>A)b 3 250_251insCAAA (7) 27 R1300X (3898C>T) (12) N96K (288C>A) R1300Q (3899G>A) (11) 302 ϩ 26 GϾA (13) 28 P1380L (4139CϾT) (14) 4 P143L (428C>T) (10) P1401P (4203CϾA) (15) 5 R152Q (455G>A) (4) 4253 ϩ 43GϾA (12) 6 571-1GϾT (4) 29 4253 ϩ 13GϾA (12) R212H (635G>A) (16) 4354-38GϾA (4) C230S (688T>A) (12) 30a 4466 ϩ 3GϾA (4) 641delG (9) 30b C1490Y (4469G>A) (17) 10 1240-14CϾT (13) P1512R (4535C>G) (4) H423R (1268ϾG) (13) 31 T1526M (4577C>T) (14) 1357 ϩ 11delG (16) 33/34 A1598D (4793C>A) (4) H423H (1269CϾT) (13) 35 4947delC (14) 11 1387delTT (4) 5018 ؉ 2T>C (7) R500R (1500GϾA) (4) 39 H1838Y (5512C>T) (14) 12 L541P (1622T>C) (14) 40 N1868I (5603AϾT) (13) R572Q (1715G>A) (17) L1894L (5682GϾC) (15) 13 Y639X (1917C>G) (17) 5714 ؉ 5G>A C641S (1922G>C) (4) 41 L1938L (5814AϾG) (12) 14 R653C (1957C>T) (12) 42 5836-43CϾA W700X (2099G>A) (4) 5836-11GϾA (15) 3607 ϩ 49TϾC P1948I (5843CϾT) (15) 15 V767D (2300T>A) (7) P1948P (5844AϾG) (15) 16 W821R (2461T>A) (14) G1961E (5882G>A) (14) 17 2588-33CϾTb 43 L1970F (5908C>T) (11) G863A (2588G>C) (17) 44 6006-16AϾG (16) 18 2654-36CϾT (4) I2023I (6069CϾT) (14) T897I (2690C>T) (7) L2027F (6079C>T) (14) 19 R943Q (2828GϾA) (13) 45 V2050L (6148G>C) (14) Y954D (2860T>G) (4) 46 R2107H (6320G>A) (18) N965S (2894A>G) (14) 6386 ؉ 2G>C (10) 20 G978D (2933G>A) (4) 47 R2139W (6415C>T) (14) L988L (2964CϾT) (4) R2149L (6446G>T) (4) 21 E1022K (3064G>A) (4) C2150Y (6449G>A) (19) A1038V (3113C>T) (14) 48 D2177N (6529G>A) (17) G1050D (3149G>A) (4) L2241V (6721C>G) (12) 3211_3212insGT (14) 6729 ϩ 21CϾT (15) 22 E1087K (3259G>A) (14) 49 6730-3TϾC (15) R1098C (3292C>T) (12) S2255I (6764GϾT) (13) S1099P (3295T>C) (4) 6816 ϩ 28GϾC (4) R1108C (3322C>T) (14) R1129L (3386G>T) (17) a Bold indicates disease-causing mutations. Login to comment
34 Exon Genotypesa Exon Genotypesa 1b M1V (1A>G) (11) 24 3523-28Tb0e;C (12) R18W (52C>T) (11) 25 G1203D (3608G>A)b 3 250_251insCAAA (7) 27 R1300X (3898C>T) (12) N96K (288C>A) R1300Q (3899G>A) (11) 302 af9; 26 Gb0e;A (13) 28 P1380L (4139Cb0e;T) (14) 4 P143L (428C>T) (10) P1401P (4203Cb0e;A) (15) 5 R152Q (455G>A) (4) 4253 af9; 43Gb0e;A (12) 6 571-1Gb0e;T (4) 29 4253 af9; 13Gb0e;A (12) R212H (635G>A) (16) 4354-38Gb0e;A (4) C230S (688T>A) (12) 30a 4466 af9; 3Gb0e;A (4) 641delG (9) 30b C1490Y (4469G>A) (17) 10 1240-14Cb0e;T (13) P1512R (4535C>G) (4) H423R (1268b0e;G) (13) 31 T1526M (4577C>T) (14) 1357 af9; 11delG (16) 33/34 A1598D (4793C>A) (4) H423H (1269Cb0e;T) (13) 35 4947delC (14) 11 1387delTT (4) 5018 d19; 2T>C (7) R500R (1500Gb0e;A) (4) 39 H1838Y (5512C>T) (14) 12 L541P (1622T>C) (14) 40 N1868I (5603Ab0e;T) (13) R572Q (1715G>A) (17) L1894L (5682Gb0e;C) (15) 13 Y639X (1917C>G) (17) 5714 d19; 5G>A C641S (1922G>C) (4) 41 L1938L (5814Ab0e;G) (12) 14 R653C (1957C>T) (12) 42 5836-43Cb0e;A W700X (2099G>A) (4) 5836-11Gb0e;A (15) 3607 af9; 49Tb0e;C P1948I (5843Cb0e;T) (15) 15 V767D (2300T>A) (7) P1948P (5844Ab0e;G) (15) 16 W821R (2461T>A) (14) G1961E (5882G>A) (14) 17 2588-33Cb0e;Tb 43 L1970F (5908C>T) (11) G863A (2588G>C) (17) 44 6006-16Ab0e;G (16) 18 2654-36Cb0e;T (4) I2023I (6069Cb0e;T) (14) T897I (2690C>T) (7) L2027F (6079C>T) (14) 19 R943Q (2828Gb0e;A) (13) 45 V2050L (6148G>C) (14) Y954D (2860T>G) (4) 46 R2107H (6320G>A) (18) N965S (2894A>G) (14) 6386 d19; 2G>C (10) 20 G978D (2933G>A) (4) 47 R2139W (6415C>T) (14) L988L (2964Cb0e;T) (4) R2149L (6446G>T) (4) 21 E1022K (3064G>A) (4) C2150Y (6449G>A) (19) A1038V (3113C>T) (14) 48 D2177N (6529G>A) (17) G1050D (3149G>A) (4) L2241V (6721C>G) (12) 3211_3212insGT (14) 6729 af9; 21Cb0e;T (15) 22 E1087K (3259G>A) (14) 49 6730-3Tb0e;C (15) R1098C (3292C>T) (12) S2255I (6764Gb0e;T) (13) S1099P (3295T>C) (4) 6816 af9; 28Gb0e;C (4) R1108C (3322C>T) (14) R1129L (3386G>T) (17) a Bold indicates disease-causing mutations. Login to comment

PMID: 15223829 [PubMed] Kang Derwent JJ et al: "Dark adaptation of rod photoreceptors in normal subjects, and in patients with Stargardt disease and an ABCA4 mutation."

No. Sentence Comment

53 Description of Subjects Subject Number Age* Sex ABCA4 Variation Dark-Adapted Maximum Peak a-Wave Amplitude (␮V)† Normal subjects 101 55 M - -243 102 37 F - -410 103 26 M - -188 104 23 F - -397 105 56 F - -268 111 29 F - -362 112 23 M - -410 -325 Ϯ 91 Stargardt patients 106 50 F val849ala, arg2107his -201 107 41 M gly1961glu, arg2077trp -306 108 22 M ala60val, 1 bp ins codon 1513 -82 109 34 M leu541pro/ala1038val,‡ gly1961glu -277 110 51 M gly1961glu -191 -211 Ϯ 87 * Age on the date of determination of the a-wave result shown in the right-hand column. Login to comment
56 ‡ leu541pro and ala1038val are commonly found together on the same allele. Login to comment

PMID: 15017103 [PubMed] Simonelli F et al: "Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family."

No. Sentence Comment

89 Finally, a homozygous complex allele L541P/A1038V has been associated with both CRD [13] and STGD [32] phenotype. Login to comment

PMID: 14517951 [PubMed] Jaakson K et al: "Genotyping microarray (gene chip) for the ABCR (ABCA4) gene."

No. Sentence Comment

115 Mutations Detected in theTwoTest Populations by the ABCR400 Array,That Had Not Been Found by SSCP Number Nucleotide change Protein e¡ect Number of cases 1 161G4A C54Y 3 2 194G4A G65E 1 3 428C4T P143L 1 4 455G4A R152Q 1 5 514G4A G172S 1 6 635G4A R212H 1 7 656G4C R219T 1 8 768G4Ta Splice/V256V 3 9 1007C4G S336C 2 10 1268A4G H423R 4 11 1411G4A E471K 2 12 1622T4Ca L541P 8 13 1933G4A D645N 1 14 2041C4T R681X 5 15 2090G4A W697X 1 16 2471T4C I824T 1 17 2588G4Ca Splice/G863A 5 18 2828G4A R943Q 1 19 2966T4C V989A 1 20 2971G4C G991R 1 21 4139C4T P1380L 8 22 4195G4A E1399K 1 23 4328G4A R1443H 1 24 4457C4T P1486L 1 25 4462T4Ca C1488R 1 26 4469G4Aa C1490Y 1 27 4918C4Ta R1640W 2 28 IVS40+5G4A Splice 2 29 5537T4C I1846T 2 30 5882G4A G1961E 5 31 6089G4A R2030Q 1 32 6104T4C L2035P 1 33 6449G4A C2150Y 1 Mutation numbering is based on the cDNA sequence (GenBank NM_000350). Login to comment
130 A similar trend was observed for the IVS38-10T>C and 1622T>C; 3113C>T (L541P;A1038V) alleles. Login to comment
155 These calculations also assume that all ''major`` alleles have been found in European populations, for example 2588G>C (G863A/delG863) in the Dutch and 1622T>C; 3113C>T (L541P;A1038V) in Germans. Login to comment

PMID: 12960208 [PubMed] Michaelides M et al: "The genetics of inherited macular dystrophies."

No. Sentence Comment

335 It is currently believed that: (1) homozygous null mutations cause the most severe phenotype of autosomal recessive RP; (2) combinations of a null mutation with a moderate missense mutation result in autosomal recessive CORD, and (3) combinations of null/mild missense or two moderate missense mutations cause STGD/FFM.28 Assessment of functional activity of mutant ABCA4 transporter has been performed by Sun et al.27 For example the missense mutations, L541P and G1961E, are associated with severely reduced but not abolished ATPase activity, whereas nonsense mutations would be predicted to have a more severe effect on protein function. Login to comment

PMID: 12796258 [PubMed] Fishman GA et al: "ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy."

No. Sentence Comment

83 Maugeri et al10 commented that a complex allele consisting of Ala1038Val and Leu541Pro variations on the same allele was found exclusively in their German patients (6 of 14). Login to comment
94 Patients With Cone-Rod Dystrophy Patient No./ Age, y/Sex Race/ Ethnicity Visual Acuity Visual Field Fundus Type* Mutation Cone vs Rod ERG ReductionOD OS 1/74/F AA 20/60 - 2 5/600 Central and peripheral loss 1 Gly1448Arg C = R 2/35/F W 10/350 5/400 Central and peripheral loss 1 Ala1038Val Leu541Pro C = R 3/42/F H 20/400 20/400 Central and peripheral loss 1 Ala1038Val Trp1618stop C = R 4/54/F W 10/180 10/140 Central scotoma 1 Donor splice, 5bp3Ј g-a intron 40 C = R 5/36/F W 10/120 10/60 - 1 Central scotoma 1 Leu541Pro Asp600Tyr C ↓ R 6/49/F W 5/160 5/180 Central and peripheral loss 1 Donor splice 5bp3Ј g-a intron 40 C = R 7/49/F W 10/350 4/350 Central and peripheral loss 1 Glu328Stop Val767Asp C = R 8/40/M W 10/225 20/400 Central and peripheral loss 1 Ala1038Val C = R 9/36/M W 5/600 5/350 Central and peripheral loss 1 Gly550Arg C = R 10/39/F AA 20/100 - 2 20/400 Central scotoma 1 Ala1038Val C = R 11/26/F W 20/200 20/200 Central and peripheral loss 1 Val2050Leu C ↓ R 12/36/M W 20/200 20/80+1 Central scotoma 1 Donor splice 5bp3Ј g-a intron 40 C = R 13/43/M AA 20/400 20/200 Central and peripheral loss 2 Leu1201Arg C = R (ND) 14/33/M P 20/40+1 20/50 Central scotoma 2 Leu2027Phe C ↓ R 15/44/M AA CF 20/400 Central and peripheral loss 2 Leu1201Arg C = R (ND) 16/56/M AA 20/40 20/40 Central scotoma 2 Leu2027Phe C = R Abbreviations: AA, African American; C ↓ R, cone responses more reduced than rod amplitudes; C = R, cone and rod amplitudes were similarly reduced; CF, counting fingers; ERG, electroretinogram; H, Hispanic; ND, nondetectable; P, Palestinian; W, white. Login to comment

PMID: 12192456 [PubMed] Gerth C et al: "Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation."

No. Sentence Comment

4 The effect of the 2588G→C mutation, the G1961E mutation, and the complex mutation L541P-A1038V depended on the mutation in the second allele. Login to comment
81 Patient 2 had a Table 2 Identified mutations in the ABCR alleles in the 16 patients (ND not tested) Patient ABCA4 allele 1 ABCA4 allele 2 no./sex (1*) Nucleotide changes Effects Nucleotide changes Effects 1a/F (139) 5917delG Frameshift 5917delG Frameshift 1b/F(139b) 5917delG Frameshift 5882G→A G1961E 2/M (167) IVS 40+5G→A Splice 4463G→A C1488Y 3/F (108) IVS 40+5G→A Splice 1086T→A Y362X 4/M (109) 1622T!92;C- L541P-A1038V 2564G→A W855X 3113C→T 5/F (113) 1622T→C- L541P-A1038V 2588G→C Splice 3113C→T 6/M (50) 2588G→C Splice 3113C→T A1038V 7b/M (138) 2588G→C Splice IVS13+1G→A Splice 7a/F Not tested Splice Not tested Splice 8/F (111) 5882G→A G1961E 2292delT-2295T→G Frameshift-S765R 9/F (147) 5882G→A G1961E IVS36+1G→A Splice 10/F (41) 5882G→A G1961E 2041C→T R681X 11a/F (114) 5882G→A G1961E 6609C→A Y2203X 11b/M ND ND 12/F (148) 3292C→T R1097C 6609C→A Y2203X 13/M (107) 3528insTGCA Frameshift 2291G→A C764Y* Refers to the patients` ID in [42] Table3Demographicdataandclinicalfeaturesofthe16patients(NDtestnotdone,Aabnormal,Nnormal,RreducedArdenratio,NRnotreliable,NAmfERGnotanalyz- able,+present,-absent,DCdarkchoroid,DDdiscdiameter) Pat.aAgeDiseaseVisualacuityColorFun-GanzfeldERGEOGmfERGStatictwo-colorKineticperimetryAngio-FundusAF atdurationvisiondusbthresholdperimetrygraphy onset/(years)ODOSRodMaximalConePeakResponseCentralCon-CentralCircularPeri- examresponseresponseresponsetimesdensitiesMeanRSLMeanCSLscotomacentricAFAFmacular/ b-wavecb-wavec30Hzab-abnormalc(dB)e(dB)efortargetcon-AF flickerdnormaldstriction <=13°>13°<=13°>13° 1a5/10520/250*20/250NDIfNDNANAND-ND-NRNRND+-- 1b32/32020/30*20/30NDINDNNNDN5-10°ND-ND-NDNDND+-- 27/15820/10020/200*AIINNNND5-15°5-25°2120--ND+-+ 39/13420/250*20/250AIINNNN5-15°5-25°0030I-2e-ND+++ 47/12520/25020/250*AIIINNNN5-25°5-25°ND-ND-I-4e-ND>1DD-- 520/4525<20/400<20/400*AIIINNNNNANA194143II-3e+ND>1DD-+ 614/19520/200*20/200AIINDNNNR5-10°5-25°1080I-4e-ND+-+ 7b16/23720/25020/250*AIINDNNR20°5-25°101113I-3e-ND+-+ 7a6/272120/20020/200NDIINDNDNDNDND-ND-ND-NDNDNDND 815/18320/100*20/100AINNND5-10°5-25°2010I-2e-N++- 921/23220/40*20/200AINDNNN10-15°5°0060NDNDN+++ 1024/31720/400*20/400AIINNNN5°5-15°3270I-2e-ND+-+ 11a16/331720/200*20/200AIINDNNNN5-15°81140I-2e-NDND 11b26/28220/20020/200*AINNNN5-10°,5-10°0010I-2e-ND+++ 20-25° 1238/571920/22*20/250NDIII(OD)ND5-25°5-25°35/3835/39ND-III/4e-NDND 1314/16220/100*20/100AIINDNNNN5-25°1120ND-DC+-+ aOnenumberindicatesonefamily bReferredtoTable1 cResults<5thpercentile dResults>95thpercentile eRSL(rodsensitivityloss;500nm,darkadapted)andCSL(conesensitivityloss; 600nm,lightadapted)comparedtothe10thpercentileofnormals;mfERGrespons- eswereanalyzedforallbutthecentral(1°inradius)responseduetohighnoise fRetinalvesselattenuation *EyetestedformfERG/staticperimetry CSL within 13° and a more widespread RSL over the 30° test field. Login to comment
84 Patients with the complex mutation L541P-A1038V Two patients were compound heterozygous for this complex mutation and a nonsense mutation (W855X, patient 4) as well as a mutation with bipartite outcome [2588G→C (G863A/G863del), patient 5]. Login to comment
91 Patients with the missense mutation 2588G→C Four patients were compound heterozygous for this missense mutation and an alteration in the donor splice site of exon 13 (IVS13+1G→A, siblings 7a and 7b), a complex mutation [L541P-A1038V (patient 5, results described above)] or a missense mutation (A1038V, patient 6). Login to comment
158 The slightly more advanced cone dysfunction in patient 3 could be caused by the more severe functional restrictions of the associated nonsense mutation (Y362X), which results in a non-functional gene product. Login to comment
159 The complex mutation L541P-A1038V was associated with an earlier onset and more rapid progression when occurring together with the W855X nonsense mutation (patient 4) than with the missense mutation 2588G→C (patient 5). Login to comment
160 Both mutations on their own, L541P and A1038V, have been associated with severely reduced but not abolished ATPase activity [49]. Login to comment

PMID: 11923272 [PubMed] Scholl HP et al: "Alterations of slow and fast rod ERG signals in patients with molecularly confirmed Stargardt disease type 1."

No. Sentence Comment

97 Characteristics of the 27 patients with STGD1 Patient Sex Age Onset VA (OD) VA (OS) CFC DF Mut(1) Mut(2) Slow Rod ERG Fast Rod ERG 1 M 32 9 1/50 20/400 Severe ϩϩ Q1412X R2077W 19.2 12.1 2 M 49 17 20/200 20/200 Severe ϩ 768G3T G1961E 56.1 23.8 3 M 46 30 20/40 20/200 Mild ϩ E471K G1961E 31.7 29.0 4* M 27 19 20/32 20/100 Moderate ϩ 2588G3C E1885K 35.0 45.1 5* M 31 18 20/400 20/400 Severe ϩϩ 2588G3C E1885K 36.1 39.1 6* F 29 12 20/200 20/200 Moderate ϩϩ 2588G3C E1885K 23.4 8.1 7 F 23 18 20/400 20/400 Mild ϩϩ E1399K G1977S 103.5 39.3 8 M 28 17 20/200 20/200 Mild ϩϩ R1898H G1975R 44.4 19.5 9 M 39 29 20/100 20/200 Moderate ϩ G607R G1961E 45.8 20.7 10 F 23 17 20/200 20/200 Mild - P68L S1689P 80.2 25.9 11 F 33 30 20/50 20/50 Mild - E1399K G1961E 49.8 62.0 12 M 50 42 20/400 20/64 Severe ϩϩ 2588G3C L541P/A1038V 53.8 30.2 13 M 36 25 20/40 20/32 Moderate ϩϩ 296insA A1038V 88.2 40.0 14 F 55 16 HM HM Severe ϩϩ Q635K IVS40ϩ5G3A 11.7 11.2 15 F 27 25 20/100 20/50 Moderate ϩ 2588G3C Q1412X 65.8 71.5 16 F 45 14 1/50 1/35 Severe ϩϩ L541P/A1038V S1063P 16.4 16.6 17 M 40 23 20/100 20/200 Moderate ϩ 296insA G1961E 46.1 58.3 18** M 35 15 20/400 20/400 Moderate ϩ 2588G3C Q1750X 14.1 12.9 19** M 43 14 HM HM Severe ϩϩ 2588G3C Q1750X 17.4 8.6 20 F 32 8 20/200 20/200 Severe ϩ G1961E G1961E 66.2 79.0 21 F 23 12 20/400 20/400 Mild - R212C T9591 24.6 25.3 22 F 29 9 20/200 20/200 Moderate ϩ L541P/A1038V G1961E 72.3 31.8 23 M 20 9 20/400 20/400 Moderate ϩϩ L541P/A1038V IVS40>9;5G3A 64.7 42.2 24 F 39 23 20/400 20/50 Moderate - W663X G1961E 92.6 68.8 25 F 41 36 20/200 20/64 Severe ϩ F1440V G1748R 97.2 52.7 26*** M 13 10 20/100 20/200 Moderate - R572Q/2588G3C IVS35ϩ2T3A 59.2 33.5 27*** M 16 15 20/200 20/200 Moderate ϩ R572Q/2588G3C IVS35ϩ2T3A 31.1 22.9 Age at examination (y), gender, age of onset (y), visual acuity (VA), central fundus changes (CFC), and existence and distribution of the typical white-yellow flecks (DF) are shown. Login to comment

PMID: 11857735 [PubMed] Pang CP et al: "Differential occurrence of mutations causative of eye diseases in the Chinese population."

No. Sentence Comment

165 About 20% of them have G1961E and 10% G2588C, while the L541P-A1038V complex allele appears to be a founder mutation [Rivera et al., 2000]. Login to comment

PMID: 11804194 [PubMed] Sun H et al: "Mechanistic studies of ABCR, the ABC transporter in photoreceptor outer segments responsible for autosomal recessive Stargardt disease."

No. Sentence Comment

94 Among these are L541P, predicted to reside adjacent to a transmembrane domain, and W1408R, which resides between the homologous halves of ABCR. These data suggest that ATP binding to the two NBDs is allosterically coupled to conformational changes in or near the transmembrane regions. Login to comment

PMID: 11702214 [PubMed] Fumagalli A et al: "Mutational scanning of the ABCR gene with double-gradient denaturing-gradient gel electrophoresis (DG-DGGE) in Italian Stargardt disease patients."

No. Sentence Comment

70 Mutated samples are: L541P (1622T→C) for exon 12; Y639X (1917C→A) for exon 13; R1098C (3292C→T) for exon 22; C1490Y (4469G→A) for exon 30; A1598D (4793C→A) for exon 34; R2149L (6446G→T) for exon 47 Table 2 Mutations detected in STGD patients and non-affected controls (Cases independent genomes analyzed). Login to comment

PMID: 11527935 [PubMed] Briggs CE et al: "Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration."

No. Sentence Comment

63 Specifically, Leu541Pro, Pro1380Leu, Gly1961Glu, and Leu2027Phe were not identified in any of the control individuals (P Ͻ 0.04). Login to comment
68 A rarely encountered missense change, Ala1637Thr, was interpreted as nonpathogenic because it was found in a patient (032-066) who also had two obviously null mutations determined to be allelic by segregation analysis, Lys356Ter and Gln1513(insC). Login to comment
69 Another change, Ala1038Val, was found in two patients (032-023 and 034-035), and in both cases segregation analysis showed that it was in cis with Leu541Pro, a combination also reported by Rivera et al.23 We interpreted Leu541Pro as pathogenic because it was found without the Ala1038Val change more frequently in patients than in control subjects. Login to comment
70 However, Sun et al.26 have shown abnormal ABCR function associated with either Ala1038Val or Leu541Pro, and it is therefore possible that both these changes are pathogenic in isolation. Login to comment
89 ABCR Sequence Changes Found in 118 Patients with Stargardt and 8 with CRD Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 21 Null Mutations 071-004 Met1Val ATG 3 GTC Het None 035-002* Ser84(insCAAA)30 251ins4 Het IVS36 ϩ 1G 3 A 034-039 Ser84(insCAAA)30 251ins4 Het Gly1961Glu 032-018 Arg152Ter23 CGA 3 TGA Het Arg2107Cys 032-005 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-039 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-060 [Ser278(delT); Arg1300Gln] [832delT; CGA 3 CAA] Het Pro1486Leu 032-066* Lys356Ter AAG 3 TAG Het Gln1513(insC) 032-072 - IVS13 ϩ 2T 3 C Het Val77Glu 032-073 Arg681Ter21 CGA 3 TGA Het Leu1388Pro 034-016 Ser1071(insGT)31 3212insGT Het None 032-065 Ser1071(insGT)31 3212insGT Het None 035-003 Ile1114(delC)5 3340delC Het Pro1380Leu 007-014* - IVS26 ϩ 1G 3 A Het Asn1345(insCA) 007-014* Asn1345(insCA) 4034insCA Het IVS26 ϩ 1G 3 A 032-066* Gln1513(insC) 4538insC Het Lys356Ter 032-010 Gln1513(insC) 4538insC Het None 032-024 Pro1570(delC)16 4710delC Het Gly1961Glu 032-016 Thr1721 (delAC) delete AC @ nt 5161 Het Thr1525Met 035-002* - IVS36 ϩ 1G 3 A23 Het Ser84(insCAAA) 034-031 Leu1741(del11) 5194del11 [GTGGTGGGCAT] Het Gly1961Glu 032-051 Trp1772Ter TGG 3 TGA Het None 032-022 - IVS41-2delA Het Gly1961Glu 032-081* Val1973(delG) 5917delG Hom None 034-017 Gly2100(delG) 6300delG Het Gly1961Glu 55 Missense and One In-Frame Deletion 032-020 Cys54Tyr15 TGC 3 TAC Het Gly863Ala 035-012 Cys54Tyr15 TGC 3 TAC Het Arg1108Cys 071-007 Cys54Tyr15 TGC 3 TAC Het Val935Ala 071-003 Asn58Lys AAC 3 AAG Het Leu1201Arg 032-069 Ala60Val15 GCG 3 GTG Het None 032-028 Gly65Glu16 GGA 3 GAA Het None 032-072 Val77Glu GTG 3 CAG Het IVS13 ϩ 2T 3 C 034-013 Gln190His CAG 3 CAC Het Gly1961Glu 032-076 Leu244Pro CTG 3 CCG Hom None 032-012 Pro309Arg CCA 3 CGA Het Arg1300Gln 032-054 Phe525Cys TTT 3 TGT Het Ile1846Thr 032-046 Arg537Cys CGT 3 TGT Het Val989Ala 034-038 Arg537Cys CGT 3 TGT Het Gly863Ala 032-095 Leu541Pro18 CTA 3 CCA Het None 034-022 Leu541Pro18 CTA 3 CCA Het Leu2027Phe 035-001 Leu541Pro18 CTA 3 CCA Het None 032-009 Leu541Pro18 CTA 3 CCA Het None 032-023 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 034-035 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 032-011 Ala549Pro GCC 3 CCC Het Gly1961Glu 032-044 Gly550Arg GGA 3 AGA Het None 032-085 Arg602Gln CGG 3 CAG Het Val643Met 032-090 Gly607Arg GGG 3 AGG Het Leu2027Phe 032-085 Val643Met GTG 3 ATG Het Arg602Gln 032-042 Val767Asp30 GTC 3 GAG Het Pro1486Leu 071-006 Val767Asp30 GTC 3 GAG Het Ile1562Thr 032-014 Leu797Pro CTG 3 CCG Het Pro1486Leu 032-038 Trp821Arg18 TGG 3 AGG Het None 034-045 Ile824Thr ATC 3 ACC Het Gly1961Glu 032-056 Gly863Ala5 GGA 3 GCA Het None 032-091 Gly863Ala5 GGA 3 GCA Het None 032-020 Gly863Ala5 GGA 3 GCA Het Cys54Tyr 032-023 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-011 Gly863Ala5 GGA 3 GCA Het Cys1488Arg 034-015 Gly863Ala5 GGA 3 GCA Het Thr1525Met 034-035 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-036 Gly863Ala5 GGA 3 GCA Het Cys2150Arg 034-038 Gly863Ala5 GGA 3 GCA Het Arg537Cys 071-007 Val935Ala GTA 3 GCA Het Cys54Tyr 032-043 Arg943Trp CGG 3 TGG Het Arg1108Leu 032-046 Val989Ala GTT 3 GCT Het Arg537Cys 071-005 Arg1108Cys18 CGC 3 TGC Het None Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 035-012 Arg1108Cys18 CGC 3 TGC Het Cys54Tyr 032-043 Arg1108Leu5 CGC 3 CTC Het Arg943Trp 032-097 Glu1122Lys18 GAG 3 AAG Het None 035-019 Glu1122Lys18 GAG 3 AAG Het None 071-003 Leu1201Arg15 CTG 3 CGG Het Asn58Lys 032-012 Arg1300Gln CGA 3 CAA Het Pro309Arg 032-068 Arg1300Gln CGA 3 CAA Het None 032-013 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-015 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-027 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 071-001 Pro1380Leu15 CCG 3 CTG Hom None 034-020 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-028 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 034-044 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-048 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 035-003 Pro1380Leu15 CCG 3 CTG Het Ile1114(delC) 032-073 Leu1388Pro CTG 3 CCG Het Arg681Ter 034-040 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 035-013 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 032-060 Pro1486Leu20 CCA 3 CTA Het [Ser278(delT); Arg1300Gln] 032-014 Pro1486Leu20 CCA 3 CTA Het Leu797Pro 032-025 Pro1486Leu20 CCA 3 CTA Het Asp1531Asn 032-042 Pro1486Leu20 CCA 3 CTA Het Val767Asp 034-011 Cys1488Arg15 TGC 3 CGC Het Gly863Ala 032-034 Cys1490Tyr15 TGC 3 TAC Het Ile1846Thr 032-084 Thr1525Met15 ACG 3 ATG Het Arg2139Trp 032-016 Thr1525Met15 ACG 3 ATG Het Thr1721(delAC) 032-021 Thr1525Met15 ACG 3 ATG Het None 032-041 Thr1525Met15 ACG 3 ATG Het None 034-015 Thr1525Met15 ACG 3 ATG Het Gly863Ala 032-049 Asp1531Asn15 GAC 3 AAC Het Gly1961Glu 034-019 Asp1531Asn15 GAC 3 AAC Het None 032-025 Asp1531Asn15 GAC 3 AAC Het Pro1846Leu 071-006 Ile1562Thr27 ATT 3 ACT Het Val767Asp 034-040 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 035-013 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 032-030* Arg1640Gln CGG 3 CAG Hom None 032-019 Pro1776Leu CCC 3 CTC Het Gly1961Glu 032-034 Ile1846Thr21 ATT 3 ACT Het Cys1490Tyr 032-054 Ile1846Thr21 ATT 3 ACT Het Phe525Cys 032-011 Gly1961Glu27 GGA 3 GAA Het Ala549Pro 032-013 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-015 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-019 Gly1961Glu27 GGA 3 GAA Het Pro1776Leu 032-022 Gly1961Glu27 GGA 3 GAA Het IVS41-2delA 032-024 Gly1961Glu27 GGA 3 GAA Het Pro1570(delC) 032-027 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-040 Gly1961Glu27 GGA 3 GAA Het None 032-049 Gly1961Glu27 GGA 3 GAA Het Asp1531Asn 034-013 Gly1961Glu27 GGA 3 GAA Het Gln190His 034-017 Gly1961Glu27 GGA 3 GAA Het Gly2100(delG) 034-021 Gly1961Glu27 GGA 3 GAA Het None 034-025 Gly1961Glu27 GGA 3 GAA Het None 034-028 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 034-031 Gly1961Glu27 GGA 3 GAA Het Leu1741(del11) 034-033 Gly1961Glu27 GGA 3 GAA Het None 034-039 Gly1961Glu27 GGA 3 GAA Het Ser84(insCAAA) 032-050 Gly1961Glu27 GGA 3 GAA Het None 034-045 Gly1961Glu27 GGA 3 GAA Het Ile824Thr 034-048 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-003 Gly1977Ser15 GGC 3 AGC Het Leu2027Phe 032-003 Leu2027Phe5 CTC 3 TTC Het Gly1977Ser 032-090 Leu2027Phe5 CTC 3 TTC Het Gly607Arg 034-006 Leu2027Phe5 CTC 3 TTC Het None 034-020 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 034-022 Leu2027Phe5 CTC 3 TTC Het Leu541Pro 034-044 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 035-011 Leu2027Phe5 CTC 3 TTC Het None 032-063 Arg2030Gln15 CGA 3 CAA Het None 032-093 Arg2030Gln15 CGA 3 CAA Het None 2232 Briggs et al. IOVS, September 2001, Vol. 42, No. Login to comment
62 Specifically, Leu541Pro, Pro1380Leu, Gly1961Glu, and Leu2027Phe were not identified in any of the control individuals (P b0d; 0.04). Login to comment
88 ABCR Sequence Changes Found in 118 Patients with Stargardt and 8 with CRD Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 21 Null Mutations 071-004 Met1Val ATG 3 GTC Het None 035-002* Ser84(insCAAA)30 251ins4 Het IVS36 af9; 1G 3 A 034-039 Ser84(insCAAA)30 251ins4 Het Gly1961Glu 032-018 Arg152Ter23 CGA 3 TGA Het Arg2107Cys 032-005 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-039 Ala222(del13bp) 666del13 [AAAGACGGTGCGC] Het None 032-060 [Ser278(delT); Arg1300Gln] [832delT; CGA 3 CAA] Het Pro1486Leu 032-066* Lys356Ter AAG 3 TAG Het Gln1513(insC) 032-072 - IVS13 af9; 2T 3 C Het Val77Glu 032-073 Arg681Ter21 CGA 3 TGA Het Leu1388Pro 034-016 Ser1071(insGT)31 3212insGT Het None 032-065 Ser1071(insGT)31 3212insGT Het None 035-003 Ile1114(delC)5 3340delC Het Pro1380Leu 007-014* - IVS26 af9; 1G 3 A Het Asn1345(insCA) 007-014* Asn1345(insCA) 4034insCA Het IVS26 af9; 1G 3 A 032-066* Gln1513(insC) 4538insC Het Lys356Ter 032-010 Gln1513(insC) 4538insC Het None 032-024 Pro1570(delC)16 4710delC Het Gly1961Glu 032-016 Thr1721 (delAC) delete AC @ nt 5161 Het Thr1525Met 035-002* - IVS36 af9; 1G 3 A23 Het Ser84(insCAAA) 034-031 Leu1741(del11) 5194del11 [GTGGTGGGCAT] Het Gly1961Glu 032-051 Trp1772Ter TGG 3 TGA Het None 032-022 - IVS41-2delA Het Gly1961Glu 032-081* Val1973(delG) 5917delG Hom None 034-017 Gly2100(delG) 6300delG Het Gly1961Glu 55 Missense and One In-Frame Deletion 032-020 Cys54Tyr15 TGC 3 TAC Het Gly863Ala 035-012 Cys54Tyr15 TGC 3 TAC Het Arg1108Cys 071-007 Cys54Tyr15 TGC 3 TAC Het Val935Ala 071-003 Asn58Lys AAC 3 AAG Het Leu1201Arg 032-069 Ala60Val15 GCG 3 GTG Het None 032-028 Gly65Glu16 GGA 3 GAA Het None 032-072 Val77Glu GTG 3 CAG Het IVS13 af9; 2T 3 C 034-013 Gln190His CAG 3 CAC Het Gly1961Glu 032-076 Leu244Pro CTG 3 CCG Hom None 032-012 Pro309Arg CCA 3 CGA Het Arg1300Gln 032-054 Phe525Cys TTT 3 TGT Het Ile1846Thr 032-046 Arg537Cys CGT 3 TGT Het Val989Ala 034-038 Arg537Cys CGT 3 TGT Het Gly863Ala 032-095 Leu541Pro18 CTA 3 CCA Het None 034-022 Leu541Pro18 CTA 3 CCA Het Leu2027Phe 035-001 Leu541Pro18 CTA 3 CCA Het None 032-009 Leu541Pro18 CTA 3 CCA Het None 032-023 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 034-035 [Leu541Pro18 ; Ala1038Val27 ] [CTA 3 CCA; GCC 3 GTC] Het Gly863Ala 032-011 Ala549Pro GCC 3 CCC Het Gly1961Glu 032-044 Gly550Arg GGA 3 AGA Het None 032-085 Arg602Gln CGG 3 CAG Het Val643Met 032-090 Gly607Arg GGG 3 AGG Het Leu2027Phe 032-085 Val643Met GTG 3 ATG Het Arg602Gln 032-042 Val767Asp30 GTC 3 GAG Het Pro1486Leu 071-006 Val767Asp30 GTC 3 GAG Het Ile1562Thr 032-014 Leu797Pro CTG 3 CCG Het Pro1486Leu 032-038 Trp821Arg18 TGG 3 AGG Het None 034-045 Ile824Thr ATC 3 ACC Het Gly1961Glu 032-056 Gly863Ala5 GGA 3 GCA Het None 032-091 Gly863Ala5 GGA 3 GCA Het None 032-020 Gly863Ala5 GGA 3 GCA Het Cys54Tyr 032-023 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-011 Gly863Ala5 GGA 3 GCA Het Cys1488Arg 034-015 Gly863Ala5 GGA 3 GCA Het Thr1525Met 034-035 Gly863Ala5 GGA 3 GCA Het [Leu541Pro; Ala1038Val] 034-036 Gly863Ala5 GGA 3 GCA Het Cys2150Arg 034-038 Gly863Ala5 GGA 3 GCA Het Arg537Cys 071-007 Val935Ala GTA 3 GCA Het Cys54Tyr 032-043 Arg943Trp CGG 3 TGG Het Arg1108Leu 032-046 Val989Ala GTT 3 GCT Het Arg537Cys 071-005 Arg1108Cys18 CGC 3 TGC Het None IOVS, September 2001, Vol. 42, No. 10 ABCR in Stargardt Macular Degeneration Patient ID Mutations (Amino Acid Based) Sequence Change (Nucleotide Based) Het/Hom Other Sequence Changes 035-012 Arg1108Cys18 CGC 3 TGC Het Cys54Tyr 032-043 Arg1108Leu5 CGC 3 CTC Het Arg943Trp 032-097 Glu1122Lys18 GAG 3 AAG Het None 035-019 Glu1122Lys18 GAG 3 AAG Het None 071-003 Leu1201Arg15 CTG 3 CGG Het Asn58Lys 032-012 Arg1300Gln CGA 3 CAA Het Pro309Arg 032-068 Arg1300Gln CGA 3 CAA Het None 032-013 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-015 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 032-027 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 071-001 Pro1380Leu15 CCG 3 CTG Hom None 034-020 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-028 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 034-044 Pro1380Leu15 CCG 3 CTG Het Leu2027Phe 034-048 Pro1380Leu15 CCG 3 CTG Het Gly1961Glu 035-003 Pro1380Leu15 CCG 3 CTG Het Ile1114(delC) 032-073 Leu1388Pro CTG 3 CCG Het Arg681Ter 034-040 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 035-013 Trp1408Arg15 TGG 3 CGG Het Arg1640Trp 032-060 Pro1486Leu20 CCA 3 CTA Het [Ser278(delT); Arg1300Gln] 032-014 Pro1486Leu20 CCA 3 CTA Het Leu797Pro 032-025 Pro1486Leu20 CCA 3 CTA Het Asp1531Asn 032-042 Pro1486Leu20 CCA 3 CTA Het Val767Asp 034-011 Cys1488Arg15 TGC 3 CGC Het Gly863Ala 032-034 Cys1490Tyr15 TGC 3 TAC Het Ile1846Thr 032-084 Thr1525Met15 ACG 3 ATG Het Arg2139Trp 032-016 Thr1525Met15 ACG 3 ATG Het Thr1721(delAC) 032-021 Thr1525Met15 ACG 3 ATG Het None 032-041 Thr1525Met15 ACG 3 ATG Het None 034-015 Thr1525Met15 ACG 3 ATG Het Gly863Ala 032-049 Asp1531Asn15 GAC 3 AAC Het Gly1961Glu 034-019 Asp1531Asn15 GAC 3 AAC Het None 032-025 Asp1531Asn15 GAC 3 AAC Het Pro1846Leu 071-006 Ile1562Thr27 ATT 3 ACT Het Val767Asp 034-040 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 035-013 Arg1640Trp18 CGG 3 TGG Het Trp1408Arg 032-030* Arg1640Gln CGG 3 CAG Hom None 032-019 Pro1776Leu CCC 3 CTC Het Gly1961Glu 032-034 Ile1846Thr21 ATT 3 ACT Het Cys1490Tyr 032-054 Ile1846Thr21 ATT 3 ACT Het Phe525Cys 032-011 Gly1961Glu27 GGA 3 GAA Het Ala549Pro 032-013 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-015 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-019 Gly1961Glu27 GGA 3 GAA Het Pro1776Leu 032-022 Gly1961Glu27 GGA 3 GAA Het IVS41-2delA 032-024 Gly1961Glu27 GGA 3 GAA Het Pro1570(delC) 032-027 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-040 Gly1961Glu27 GGA 3 GAA Het None 032-049 Gly1961Glu27 GGA 3 GAA Het Asp1531Asn 034-013 Gly1961Glu27 GGA 3 GAA Het Gln190His 034-017 Gly1961Glu27 GGA 3 GAA Het Gly2100(delG) 034-021 Gly1961Glu27 GGA 3 GAA Het None 034-025 Gly1961Glu27 GGA 3 GAA Het None 034-028 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 034-031 Gly1961Glu27 GGA 3 GAA Het Leu1741(del11) 034-033 Gly1961Glu27 GGA 3 GAA Het None 034-039 Gly1961Glu27 GGA 3 GAA Het Ser84(insCAAA) 032-050 Gly1961Glu27 GGA 3 GAA Het None 034-045 Gly1961Glu27 GGA 3 GAA Het Ile824Thr 034-048 Gly1961Glu27 GGA 3 GAA Het Pro1380Leu 032-003 Gly1977Ser15 GGC 3 AGC Het Leu2027Phe 032-003 Leu2027Phe5 CTC 3 TTC Het Gly1977Ser 032-090 Leu2027Phe5 CTC 3 TTC Het Gly607Arg 034-006 Leu2027Phe5 CTC 3 TTC Het None 034-020 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 034-022 Leu2027Phe5 CTC 3 TTC Het Leu541Pro 034-044 Leu2027Phe5 CTC 3 TTC Het Pro1380Leu 035-011 Leu2027Phe5 CTC 3 TTC Het None 032-063 Arg2030Gln15 CGA 3 CAA Het None 032-093 Arg2030Gln15 CGA 3 CAA Het None 2232 Briggs et al. IOVS, September 2001, Vol. 42, No. 10 TABLE 1 (continued). Login to comment

PMID: 11328755 [PubMed] Scholl HP et al: "L- and M-cone-driven electroretinograms in Stargardt's macular dystrophy-fundus flavimaculatus."

No. Sentence Comment

43 Characteristics of the Patients with SMD-FF Patient Sex Age (y) Age at Onset (y) VA CFC DF CV Exon (1) Mut (1) Exon (2) Mut (2) 1 M 32 29 0.6 Moderate ϩ Normal 48 L2241V NF 2 F 39 23 0.4 Moderate - Chaotic 14 W663X 42 G1961E 3 M 34 16 0.1 Moderate ϩ - 42 G1961E NF 4 M 49 17 0.1 Severe ϩ NP 6 G768T/splice 42 G1961E 5 F 36 35 0.6 Moderate ϩ VS (T) 6 C230S 42 G1961E 6 M 28 17 0.1 Mild ϩϩ INS 40 R1898H 43 G1975R 7 M 20 9 0.05 Moderate ϩϩ VS (P/D) 12 ϩ 21 L541P ϩ A1038V 40 IVS40 ϩ 5G 3 A 8 M 33 6 0.1 Mild - Chaotic NF NF 9 M 39 29 0.2 Moderate ϩ VS (P/D) 13 G607R 42 G1961E 10 M 38 22 0.1 Severe ϩ Chaotic NF NF 11 F 28 20 0.7 Mild ϩϩ INS 3 A60T 40 R1898H 12 M 46 30 0.5 Mild ϩ Chaotic 11 E471K 42 G1961E 13 F 25 11 0.1 Moderate ϩϩ S 17 G863A NF 14 F 51 41 0.8 Moderate ϩϩ NP 40 R1898H NF 15 F 23 17 0.1 Mild - Chaotic 3 P68L 36 S1689P 16 F 33 30 0.4 Mild - Chaotic 28 E1399K 42 G1961E 17 F 41 36 0.1 Severe ϩ VS (T) 29 F1440V 37 G1748R 18 M 59 54 0.1 Severe ϩ VS (P/D) 42 G1961E NF 19* M 35 15 0.05 Moderate ϩ Chaotic 17 G863A 37 Q1750X 20* M 43 14 HM Severe ϩϩ NP 17 G863A 37 Q1750X 21 F 46 16 0.1 Moderate ϩ NP NF NF 22 F 32 22 0.05 Moderate ϩ INS 21 A1038V NF 23 M 50 42 0.3 Severe ϩϩ VS (P/D) 12 ϩ 21 L541P ϩ A1038V 17 G863A 24 F 30 14 0.1 Moderate ϩϩ INS 17 G863A 40 IVS40 ϩ 5G 3 A 25 M 36 25 0.5 Moderate ϩϩ - 3 296INSA 21 A1038V 26 M 40 23 0.2 Moderate ϩ S 3 296INSA 42 G1961E 27 F 35 9 0.1 Severe ϩϩ VS (P/D) 22 R1108C NF 28 F 23 18 0.05 Mild ϩϩ S 28 E1399K 43 G1977S 29 F 25 18 0.2 Mild ϩ Chaotic 37 L1763P NF 30 F 16 11 0.1 Moderate ϩ Chaotic 22 R1108C NF 31 M 40 35 0.1 Moderate ϩϩ VS (P/D) 14 R681X NF 32 F 28 27 0.1 Moderate ϩ S 12 ϩ 21 L541P ϩ A1038V 21 A1038V 33 M 32 9 0.05 Severe ϩϩ Chaotic 28 Q1412X 45 R2077W 34 F 23 21 0.2 Moderate ϩ INS 6 G768T/splice NF 35 F 38 33 FC Moderate - Chaotic 17 G863A NF 36 F 39 10 HM Severe ϩϩ NP NF NF 37 F 13 8 0.1 Moderate ϩϩ S - - 38 F 27 25 0.2 Moderate ϩ Chaotic 17 G863A 28 Q1412X 39 M 16 15 0.1 Moderate ϩ VS (P/D) 12 ϩ 17 R572Q ϩ G863A 35 IVS35 ϩ 2T 3 A 40 M 27 26 0.6 Moderate - S 17 G863A NF 41 M 18 16 0.2 Moderate ϩ - - - 42 M 25 24 0.1 Mild - - NF NF 43 F 29 9 0.1 Moderate ϩ Chaotic 12 ϩ 21 L541P ϩ A1038V 42 G1961E 44 M 39 28 0.1 Mild - NP 6 N247S NF 45 F 23 12 0.05 Mild - NP 6 R212C 19 T959I 46 M 43 36 0.2 Moderate ϩ VS (P/D) 21 A1038V NF 47 M 21 18 0.4 Mild ϩϩ INS 28 Q1412X NF Shown are age at examination, age of onset, visual acuity, central fundus changes, and existence and distribution of the typical white-yellow flecks. Login to comment
44 Characteristics of the Patients with SMD-FF Patient Sex Age (y) Age at Onset (y) VA CFC DF CV Exon (1) Mut (1) Exon (2) Mut (2) 1 M 32 29 0.6 Moderate af9; Normal 48 L2241V NF 2 F 39 23 0.4 Moderate afa; Chaotic 14 W663X 42 G1961E 3 M 34 16 0.1 Moderate af9; - 42 G1961E NF 4 M 49 17 0.1 Severe af9; NP 6 G768T/splice 42 G1961E 5 F 36 35 0.6 Moderate af9; VS (T) 6 C230S 42 G1961E 6 M 28 17 0.1 Mild af9;af9; INS 40 R1898H 43 G1975R 7 M 20 9 0.05 Moderate af9;af9; VS (P/D) 12 af9; 21 L541P af9; A1038V 40 IVS40 af9; 5G 3 A 8 M 33 6 0.1 Mild afa; Chaotic NF NF 9 M 39 29 0.2 Moderate af9; VS (P/D) 13 G607R 42 G1961E 10 M 38 22 0.1 Severe af9; Chaotic NF NF 11 F 28 20 0.7 Mild af9;af9; INS 3 A60T 40 R1898H 12 M 46 30 0.5 Mild af9; Chaotic 11 E471K 42 G1961E 13 F 25 11 0.1 Moderate af9;af9; S 17 G863A NF 14 F 51 41 0.8 Moderate af9;af9; NP 40 R1898H NF 15 F 23 17 0.1 Mild afa; Chaotic 3 P68L 36 S1689P 16 F 33 30 0.4 Mild afa; Chaotic 28 E1399K 42 G1961E 17 F 41 36 0.1 Severe af9; VS (T) 29 F1440V 37 G1748R 18 M 59 54 0.1 Severe af9; VS (P/D) 42 G1961E NF 19* M 35 15 0.05 Moderate af9; Chaotic 17 G863A 37 Q1750X 20* M 43 14 HM Severe af9;af9; NP 17 G863A 37 Q1750X 21 F 46 16 0.1 Moderate af9; NP NF NF 22 F 32 22 0.05 Moderate af9; INS 21 A1038V NF 23 M 50 42 0.3 Severe af9;af9; VS (P/D) 12 af9; 21 L541P af9; A1038V 17 G863A 24 F 30 14 0.1 Moderate af9;af9; INS 17 G863A 40 IVS40 af9; 5G 3 A 25 M 36 25 0.5 Moderate af9;af9; - 3 296INSA 21 A1038V 26 M 40 23 0.2 Moderate af9; S 3 296INSA 42 G1961E 27 F 35 9 0.1 Severe af9;af9; VS (P/D) 22 R1108C NF 28 F 23 18 0.05 Mild af9;af9; S 28 E1399K 43 G1977S 29 F 25 18 0.2 Mild af9; Chaotic 37 L1763P NF 30 F 16 11 0.1 Moderate af9; Chaotic 22 R1108C NF 31 M 40 35 0.1 Moderate af9;af9; VS (P/D) 14 R681X NF 32 F 28 27 0.1 Moderate af9; S 12 af9; 21 L541P af9; A1038V 21 A1038V 33 M 32 9 0.05 Severe af9;af9; Chaotic 28 Q1412X 45 R2077W 34 F 23 21 0.2 Moderate af9; INS 6 G768T/splice NF 35 F 38 33 FC Moderate afa; Chaotic 17 G863A NF 36 F 39 10 HM Severe af9;af9; NP NF NF 37 F 13 8 0.1 Moderate af9;af9; S - - 38 F 27 25 0.2 Moderate af9; Chaotic 17 G863A 28 Q1412X 39 M 16 15 0.1 Moderate af9; VS (P/D) 12 af9; 17 R572Q af9; G863A 35 IVS35 af9; 2T 3 A 40 M 27 26 0.6 Moderate afa; S 17 G863A NF 41 M 18 16 0.2 Moderate af9; - - - 42 M 25 24 0.1 Mild afa; - NF NF 43 F 29 9 0.1 Moderate af9; Chaotic 12 af9; 21 L541P af9; A1038V 42 G1961E 44 M 39 28 0.1 Mild afa; NP 6 N247S NF 45 F 23 12 0.05 Mild afa; NP 6 R212C 19 T959I 46 M 43 36 0.2 Moderate af9; VS (P/D) 21 A1038V NF 47 M 21 18 0.4 Mild af9;af9; INS 28 Q1412X NF Shown are age at examination, age of onset, visual acuity, central fundus changes, and existence and distribution of the typical white-yellow flecks. Login to comment

PMID: 11328725 [PubMed] Webster AR et al: "An analysis of allelic variation in the ABCA4 gene."

No. Sentence Comment

102 Thirty-Three Truncated and 98 Amino Acid-Changing Variants in the ABCA4 Gene Exon Nucleotide Change Effect (A) (B) AMD (n ‫؍‬ 182) Control (n ‫؍‬ 96) STGD (n ‫؍‬ 374) Allele Prevalence 2 106delT FS NS 0 0 1 Ͻ0.01 2 160 ϩ 1g 3 a Splice site NS 0 0 1 Ͻ0.01 3 161G 3 A Cys54Tyr NS 0 0 6 Ͻ0.01 3 179C 3 T Ala60Val NS 0 0 2 Ͻ0.01 3 194G 3 A Gly65Glu NS 0 0 2 Ͻ0.01 3 223T 3 G Cys75Gly NS 0 0 2 Ͻ0.01 3 247delCAAA FS NS 0 0 2 Ͻ0.01 3 298C 3 T Ser100Pro NS 0 0 1 Ͻ0.01 5 454C 3 T Arg152Stop NS 0 0 2 Ͻ0.01 6 574G 3 A Ala192Thr NS 0 0 1 Ͻ0.01 6 618C 3 G Ser206Arg NS 0 0 3 Ͻ0.01 6 634C 3 T Arg212Cys 0.02 Yes 0 0 7 0.01 6 635G 3 A Arg212His NS 2 2 6 0.01 6 658C 3 T Arg220Cys NS 0 0 2 Ͻ0.01 6 661delG FS NS 0 0 1 Ͻ0.01 666delAAAGACGGTGC 6 GC FS NS 0 0 1 Ͻ0.01 6 746A 3 C Asp249Gly NS 0 0 1 Ͻ0.01 8 899C 3 A Thr300Asn NS 0 0 1 Ͻ0.01 8 997C 3 T Arg333Trp NS 0 0 1 Ͻ0.01 9 1140T 3 A Asn380Lys NS 0 0 1 Ͻ0.01 9 1222C 3 T Arg408Stop NS 0 0 1 Ͻ0.01 10 1268A 3 G His423Arg NS 1 0 7 0.01 10 1335C 3 G Ser445Arg NS 0 0 1 Ͻ0.01 10 1344delG FS NS 0 0 1 Ͻ0.01 11 1411G 3 A Glu471Lys NS 0 0 3 Ͻ0.01 11 1513delATCAC FS NS 0 0 1 Ͻ0.01 12 1622T 3 C Leu541Pro 0.001 Yes 0 0 11 0.01 13 1804C 3 T Arg602Trp NS 0 0 3 Ͻ0.01 13 1805G 3 A Arg602Gln NS 0 0 1 Ͻ0.01 13 1819G 3 T Gly607Trp NS 0 0 1 Ͻ0.01 13 1823T 3 A Phe608Ile NS 0 0 1 Ͻ0.01 13 1927G 3 A Val643Met NS 0 0 1 Ͻ0.01 14 1989G 3 T Trp663Stop NS 0 0 1 Ͻ0.01 14 2005delAT FS NS 0 0 3 Ͻ0.01 14 2041C 3 T Arg681Stop NS 0 0 2 Ͻ0.01 14 2147C 3 T Thr716Met NS 0 0 1 Ͻ0.01 15 2291G 3 A Cys764Tyr NS 0 0 1 Ͻ0.01 15 2294G 3 A Ser765Asn NS 0 0 1 Ͻ0.01 15 2300T 3 A Val767Asp NS 0 0 2 Ͻ0.01 16 2385del16bp FS NS 0 0 1 Ͻ0.01 16 2453G 3 A Gly818Glu NS 0 0 1 Ͻ0.01 16 2461T 3 A Trp821Arg NS 0 0 1 Ͻ0.01 16 2546T 3 C Val849Ala NS 0 0 4 Ͻ0.01 16 2552G 3 A Gly851Asp NS 0 0 1 Ͻ0.01 16 2560G 3 A Ala854Thr NS 0 0 1 Ͻ0.01 17 2588G 3 C Gly863Ala 0.0006 No 2 2 28 0.02 17 2617T 3 C Phe873Leu NS 0 0 1 Ͻ0.01 18 2690C 3 T Thr897Ile NS 0 0 1 Ͻ0.01 18 2701A 3 G Thr901Ala NS 0 1 0 Ͻ0.01 18 2703A 3 G Thr901Arg NS 0 0 2 Ͻ0.01 19 2828G 3 A Arg943Gln NS 20 13 37 0.05 19 2883delC FS NS 0 0 1 Ͻ0.01 20 2894A 3 G Asn965Ser NS 0 0 3 Ͻ0.01 19 2912C 3 A Thr971Asn NS 0 0 1 Ͻ0.01 19 2915C 3 A Thr972Asn NS 0 0 1 Ͻ0.01 20 2920T 3 C Ser974Pro NS 0 0 1 Ͻ0.01 20 2966T 3 C Val989Ala NS 0 0 2 Ͻ0.01 20 2977del8bp FS NS 0 0 1 Ͻ0.01 20 3041T 3 G Leu1014Arg NS 0 0 1 Ͻ0.01 21 3055A 3 G Thr1019Ala NS 0 0 1 Ͻ0.01 21 3064G 3 A Glu1022Lys NS 0 0 1 Ͻ0.01 21 3091A 3 G Lys1031Glu NS 0 0 1 Ͻ0.01 21 3113G 3 T Ala1038Val 0.001 Yes 1 0 17 0.01 22 3205insAA FS NS 0 0 1 Ͻ0.01 22 3261G 3 A Glu1087Lys NS 0 0 2 Ͻ0.01 22 3322C 3 T Arg1108Cys 0.04 Yes 0 0 6 Ͻ0.01 22 3323G 3 A Arg1108His NS 0 0 1 Ͻ0.01 23 3364G 3 A Glu1122Lys NS 0 0 1 Ͻ0.01 (continues) Exon Nucleotide Change Effect (A) (B) AMD (n ‫؍‬ 182) Control (n ‫؍‬ 96) STGD (n ‫؍‬ 374) Allele Prevalence 23 3386G 3 T Arg1129Leu NS 0 0 3 Ͻ0.01 24 3531C 3 A Cys1158Stop NS 0 0 1 Ͻ0.01 25 3749T 3 C Leu1250Pro NS 0 0 1 Ͻ0.01 26 3835delGATTCT FS NS 0 0 1 Ͻ0.01 27 3940C 3 A Pro1314Thr NS 0 1 0 Ͻ0.01 28 4139C 3 T Pro1380Leu 0.001 Yes 0 0 10 0.01 28 4222T 3 C Trp1408Arg NS 0 0 2 Ͻ0.01 28 4223G 3 T Trp1408Leu NS 0 0 2 Ͻ0.01 28 4234C 3 T Gln1412stop NS 0 0 1 Ͻ0.01 29 4297G 3 A Val1433Ile NS 1 0 0 Ͻ0.01 29 4319T 3 C Phe1440Ser NS 0 0 1 Ͻ0.01 30 4353 - 1g 3 t Splice site NS 0 0 1 Ͻ0.01 30 4457C 3 T Pro1486Leu NS 0 0 1 Ͻ0.01 30 4462T 3 C Cys1488Arg NS 0 0 3 Ͻ0.01 30 4463G 3 T Cys1488Phe NS 0 0 2 Ͻ0.01 30 4469G 3 A Cys1490Tyr NS 0 0 3 Ͻ0.01 30 4531insC FS NS 0 0 2 Ͻ0.01 32 4538A 3 G Gln1513Arg NS 0 0 1 Ͻ0.01 30 4539 ϩ 1g 3 t Splice site NS 0 0 1 Ͻ0.01 31 4574T 3 C Leu1525Pro NS 0 0 1 Ͻ0.01 33 4733delGTTT FS NS 0 0 1 Ͻ0.01 4859delATAACAinsTCC 35 T FS NS 0 0 1 Ͻ0.01 36 4909G 3 A Ala1637Thr NS 0 0 1 Ͻ0.01 35 4918C 3 T Arg1640Trp NS 0 0 1 Ͻ0.01 35 4919G 3 A Arg1640Gln NS 0 0 1 Ͻ0.01 35 4954T 3 G Tyr1652Asp NS 0 0 1 Ͻ0.01 36 5077G 3 A Val1693Ile NS 0 0 1 Ͻ0.01 36 5186T 3 C Leu1729Pro NS 0 0 2 Ͻ0.01 36 5206T 3 C Ser1736Pro NS 0 0 1 Ͻ0.01 36 5212del11bp FS NS 0 0 1 Ͻ0.01 37 5225delTGGTGGTGGGC FS NS 0 0 1 Ͻ0.01 del LPA 37 5278del9bp 1760 NS 0 0 1 Ͻ0.01 37 5288delG FS NS 0 0 1 Ͻ0.01 38 5395A 3 G Asn1799Asp NS 0 0 1 Ͻ0.01 38 5451T 3 G Asp1817Glu NS 1 0 4 Ͻ0.01 39 5584 ϩ 5g 3 a Splice site 0.02 Yes 0 0 6 Ͻ0.01 40 5603A 3 T Asn1868Ile 0.0006 No 20 7 79 0.08 40 5651T 3 A Val1884GLu NS 0 0 1 Ͻ0.01 40 5657G 3 A Gly1886Glu NS 0 0 1 Ͻ0.01 40 5687T 3 A Val1896Asp NS 0 0 1 Ͻ0.01 40 5693G 3 A Arg1898His NS 0 0 1 Ͻ0.01 40 5714 ϩ 5g 3 a Splice site NS 0 0 1 Ͻ0.01 42 5843CA 3 TG Pro1948Leu NS 11 7 28 0.04 42 5882G 3 A Gly1961Glu Ͻ0.0001 Yes 1 0 43 0.03 43 5908C 3 T Leu1970Phe NS 1 0 1 Ͻ0.01 43 5917delG FS NS 0 0 1 Ͻ0.01 44 6079C 3 T Leu2027Phe 0.01 Yes 0 0 9 0.01 44 6088C 3 T Arg2030Stop NS 0 0 2 Ͻ0.01 44 6089G 3 A Arg2030Gln NS 0 0 1 Ͻ0.01 44 6112A 3 T Arg2038Trp NS 0 0 1 Ͻ0.01 45 6148A 3 C Val2050Leu NS 1 0 0 Ͻ0.01 46 6212A 3 T Tyr2071Phe NS 0 0 1 Ͻ0.01 45 6229C 3 T Arg2077Trp NS 0 0 2 Ͻ0.01 46 6320G 3 A Arg2107His 0.01 Yes 0 0 10 0.01 46 6383A 3 G His2128Arg NS 0 0 1 Ͻ0.01 47 6446G 3 T Arg2149Leu NS 0 0 1 Ͻ0.01 47 6449G 3 A Cys2150Tyr NS 0 0 5 Ͻ0.01 48 6529G 3 A Asp2177Asn NS 2 0 0 Ͻ0.01 48 6686T 3 C Leu2229Pro NS 0 0 1 Ͻ0.01 48 6707delTCACACAG FS NS 0 0 1 Ͻ0.01 48 6729 ϩ 1g 3 a Splice site NS 0 0 1 Ͻ0.01 49 6764G 3 T Ser2255Ile 0.009 No 16 4 54 0.06 49 6788G 3 T Arg2263Leu NS 0 0 1 Ͻ0.01 (A) The probability under the null hypothesis of similar prevalence of each variant in Stargardt (STGD) compared with non-STGD alleles (two-tailed Fisher`s exact test); (B) compatability of the variant existing in a ratio of 100:1 in STGD to control alleles, calculated using the binomial distribution. 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148 These included three nonconservative changes, Gly1961Glu, Arg1108Cys, and Arg212Cys, and five other changes that were conservative by our criteria, Leu541Pro, Ala1038Val, Pro1380Leu, Leu2027Phe, and Arg2107His. Login to comment
177 Similarly, Leu541Pro occurred in 10 patients with Stargardt disease who harbored the variant Ala1038Val, and, when phase could be determined, these variations were found in cis. Login to comment
178 One patient with Stargardt disease bore Leu541Pro without the Ala1038Val variant, and seven harbored the Ala1038Val change without Leu541Pro. Login to comment
179 Ala1038Val without Leu541Pro was also found in one patient with AMD. Login to comment
182 Considering only those variants predicted to cause protein truncation and missense changes compatible with disease association, we found 1 patient with five such variants, 11 with three, and a further 6 with two (Leu541Pro and Ala1038Val) that were on the same chromosome. Login to comment
103 Thirty-Three Truncated and 98 Amino Acid-Changing Variants in the ABCA4 Gene Exon Nucleotide Change Effect (A) (B) AMD (n d1d; 182) Control (n d1d; 96) STGD (n d1d; 374) Allele Prevalence 2 106delT FS NS 0 0 1 b0d;0.01 2 160 af9; 1g 3 a Splice site NS 0 0 1 b0d;0.01 3 161G 3 A Cys54Tyr NS 0 0 6 b0d;0.01 3 179C 3 T Ala60Val NS 0 0 2 b0d;0.01 3 194G 3 A Gly65Glu NS 0 0 2 b0d;0.01 3 223T 3 G Cys75Gly NS 0 0 2 b0d;0.01 3 247delCAAA FS NS 0 0 2 b0d;0.01 3 298C 3 T Ser100Pro NS 0 0 1 b0d;0.01 5 454C 3 T Arg152Stop NS 0 0 2 b0d;0.01 6 574G 3 A Ala192Thr NS 0 0 1 b0d;0.01 6 618C 3 G Ser206Arg NS 0 0 3 b0d;0.01 6 634C 3 T Arg212Cys 0.02 Yes 0 0 7 0.01 6 635G 3 A Arg212His NS 2 2 6 0.01 6 658C 3 T Arg220Cys NS 0 0 2 b0d;0.01 6 661delG FS NS 0 0 1 b0d;0.01 666delAAAGACGGTGC 6 GC FS NS 0 0 1 b0d;0.01 6 746A 3 C Asp249Gly NS 0 0 1 b0d;0.01 8 899C 3 A Thr300Asn NS 0 0 1 b0d;0.01 8 997C 3 T Arg333Trp NS 0 0 1 b0d;0.01 9 1140T 3 A Asn380Lys NS 0 0 1 b0d;0.01 9 1222C 3 T Arg408Stop NS 0 0 1 b0d;0.01 10 1268A 3 G His423Arg NS 1 0 7 0.01 10 1335C 3 G Ser445Arg NS 0 0 1 b0d;0.01 10 1344delG FS NS 0 0 1 b0d;0.01 11 1411G 3 A Glu471Lys NS 0 0 3 b0d;0.01 11 1513delATCAC FS NS 0 0 1 b0d;0.01 12 1622T 3 C Leu541Pro 0.001 Yes 0 0 11 0.01 13 1804C 3 T Arg602Trp NS 0 0 3 b0d;0.01 13 1805G 3 A Arg602Gln NS 0 0 1 b0d;0.01 13 1819G 3 T Gly607Trp NS 0 0 1 b0d;0.01 13 1823T 3 A Phe608Ile NS 0 0 1 b0d;0.01 13 1927G 3 A Val643Met NS 0 0 1 b0d;0.01 14 1989G 3 T Trp663Stop NS 0 0 1 b0d;0.01 14 2005delAT FS NS 0 0 3 b0d;0.01 14 2041C 3 T Arg681Stop NS 0 0 2 b0d;0.01 14 2147C 3 T Thr716Met NS 0 0 1 b0d;0.01 15 2291G 3 A Cys764Tyr NS 0 0 1 b0d;0.01 15 2294G 3 A Ser765Asn NS 0 0 1 b0d;0.01 15 2300T 3 A Val767Asp NS 0 0 2 b0d;0.01 16 2385del16bp FS NS 0 0 1 b0d;0.01 16 2453G 3 A Gly818Glu NS 0 0 1 b0d;0.01 16 2461T 3 A Trp821Arg NS 0 0 1 b0d;0.01 16 2546T 3 C Val849Ala NS 0 0 4 b0d;0.01 16 2552G 3 A Gly851Asp NS 0 0 1 b0d;0.01 16 2560G 3 A Ala854Thr NS 0 0 1 b0d;0.01 17 2588G 3 C Gly863Ala 0.0006 No 2 2 28 0.02 17 2617T 3 C Phe873Leu NS 0 0 1 b0d;0.01 18 2690C 3 T Thr897Ile NS 0 0 1 b0d;0.01 18 2701A 3 G Thr901Ala NS 0 1 0 b0d;0.01 18 2703A 3 G Thr901Arg NS 0 0 2 b0d;0.01 19 2828G 3 A Arg943Gln NS 20 13 37 0.05 19 2883delC FS NS 0 0 1 b0d;0.01 20 2894A 3 G Asn965Ser NS 0 0 3 b0d;0.01 19 2912C 3 A Thr971Asn NS 0 0 1 b0d;0.01 19 2915C 3 A Thr972Asn NS 0 0 1 b0d;0.01 20 2920T 3 C Ser974Pro NS 0 0 1 b0d;0.01 20 2966T 3 C Val989Ala NS 0 0 2 b0d;0.01 20 2977del8bp FS NS 0 0 1 b0d;0.01 20 3041T 3 G Leu1014Arg NS 0 0 1 b0d;0.01 21 3055A 3 G Thr1019Ala NS 0 0 1 b0d;0.01 21 3064G 3 A Glu1022Lys NS 0 0 1 b0d;0.01 21 3091A 3 G Lys1031Glu NS 0 0 1 b0d;0.01 21 3113G 3 T Ala1038Val 0.001 Yes 1 0 17 0.01 22 3205insAA FS NS 0 0 1 b0d;0.01 22 3261G 3 A Glu1087Lys NS 0 0 2 b0d;0.01 22 3322C 3 T Arg1108Cys 0.04 Yes 0 0 6 b0d;0.01 22 3323G 3 A Arg1108His NS 0 0 1 b0d;0.01 23 3364G 3 A Glu1122Lys NS 0 0 1 b0d;0.01 (continues) Exon Nucleotide Change Effect (A) (B) AMD (n d1d; 182) Control (n d1d; 96) STGD (n d1d; 374) Allele Prevalence 23 3386G 3 T Arg1129Leu NS 0 0 3 b0d;0.01 24 3531C 3 A Cys1158Stop NS 0 0 1 b0d;0.01 25 3749T 3 C Leu1250Pro NS 0 0 1 b0d;0.01 26 3835delGATTCT FS NS 0 0 1 b0d;0.01 27 3940C 3 A Pro1314Thr NS 0 1 0 b0d;0.01 28 4139C 3 T Pro1380Leu 0.001 Yes 0 0 10 0.01 28 4222T 3 C Trp1408Arg NS 0 0 2 b0d;0.01 28 4223G 3 T Trp1408Leu NS 0 0 2 b0d;0.01 28 4234C 3 T Gln1412stop NS 0 0 1 b0d;0.01 29 4297G 3 A Val1433Ile NS 1 0 0 b0d;0.01 29 4319T 3 C Phe1440Ser NS 0 0 1 b0d;0.01 30 4353 afa; 1g 3 t Splice site NS 0 0 1 b0d;0.01 30 4457C 3 T Pro1486Leu NS 0 0 1 b0d;0.01 30 4462T 3 C Cys1488Arg NS 0 0 3 b0d;0.01 30 4463G 3 T Cys1488Phe NS 0 0 2 b0d;0.01 30 4469G 3 A Cys1490Tyr NS 0 0 3 b0d;0.01 30 4531insC FS NS 0 0 2 b0d;0.01 32 4538A 3 G Gln1513Arg NS 0 0 1 b0d;0.01 30 4539 af9; 1g 3 t Splice site NS 0 0 1 b0d;0.01 31 4574T 3 C Leu1525Pro NS 0 0 1 b0d;0.01 33 4733delGTTT FS NS 0 0 1 b0d;0.01 4859delATAACAinsTCC 35 T FS NS 0 0 1 b0d;0.01 36 4909G 3 A Ala1637Thr NS 0 0 1 b0d;0.01 35 4918C 3 T Arg1640Trp NS 0 0 1 b0d;0.01 35 4919G 3 A Arg1640Gln NS 0 0 1 b0d;0.01 35 4954T 3 G Tyr1652Asp NS 0 0 1 b0d;0.01 36 5077G 3 A Val1693Ile NS 0 0 1 b0d;0.01 36 5186T 3 C Leu1729Pro NS 0 0 2 b0d;0.01 36 5206T 3 C Ser1736Pro NS 0 0 1 b0d;0.01 36 5212del11bp FS NS 0 0 1 b0d;0.01 37 5225delTGGTGGTGGGC FS NS 0 0 1 b0d;0.01 del LPA 37 5278del9bp 1760 NS 0 0 1 b0d;0.01 37 5288delG FS NS 0 0 1 b0d;0.01 38 5395A 3 G Asn1799Asp NS 0 0 1 b0d;0.01 38 5451T 3 G Asp1817Glu NS 1 0 4 b0d;0.01 39 5584 af9; 5g 3 a Splice site 0.02 Yes 0 0 6 b0d;0.01 40 5603A 3 T Asn1868Ile 0.0006 No 20 7 79 0.08 40 5651T 3 A Val1884GLu NS 0 0 1 b0d;0.01 40 5657G 3 A Gly1886Glu NS 0 0 1 b0d;0.01 40 5687T 3 A Val1896Asp NS 0 0 1 b0d;0.01 40 5693G 3 A Arg1898His NS 0 0 1 b0d;0.01 40 5714 af9; 5g 3 a Splice site NS 0 0 1 b0d;0.01 42 5843CA 3 TG Pro1948Leu NS 11 7 28 0.04 42 5882G 3 A Gly1961Glu b0d;0.0001 Yes 1 0 43 0.03 43 5908C 3 T Leu1970Phe NS 1 0 1 b0d;0.01 43 5917delG FS NS 0 0 1 b0d;0.01 44 6079C 3 T Leu2027Phe 0.01 Yes 0 0 9 0.01 44 6088C 3 T Arg2030Stop NS 0 0 2 b0d;0.01 44 6089G 3 A Arg2030Gln NS 0 0 1 b0d;0.01 44 6112A 3 T Arg2038Trp NS 0 0 1 b0d;0.01 45 6148A 3 C Val2050Leu NS 1 0 0 b0d;0.01 46 6212A 3 T Tyr2071Phe NS 0 0 1 b0d;0.01 45 6229C 3 T Arg2077Trp NS 0 0 2 b0d;0.01 46 6320G 3 A Arg2107His 0.01 Yes 0 0 10 0.01 46 6383A 3 G His2128Arg NS 0 0 1 b0d;0.01 47 6446G 3 T Arg2149Leu NS 0 0 1 b0d;0.01 47 6449G 3 A Cys2150Tyr NS 0 0 5 b0d;0.01 48 6529G 3 A Asp2177Asn NS 2 0 0 b0d;0.01 48 6686T 3 C Leu2229Pro NS 0 0 1 b0d;0.01 48 6707delTCACACAG FS NS 0 0 1 b0d;0.01 48 6729 af9; 1g 3 a Splice site NS 0 0 1 b0d;0.01 49 6764G 3 T Ser2255Ile 0.009 No 16 4 54 0.06 49 6788G 3 T Arg2263Leu NS 0 0 1 b0d;0.01 (A) The probability under the null hypothesis of similar prevalence of each variant in Stargardt (STGD) compared with non-STGD alleles (two-tailed Fisher`s exact test); (B) compatability of the variant existing in a ratio of 100:1 in STGD to control alleles, calculated using the binomial distribution. 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149 These included three nonconservative changes, Gly1961Glu, Arg1108Cys, and Arg212Cys, and five other changes that were conservative by our criteria, Leu541Pro, Ala1038Val, Pro1380Leu, Leu2027Phe, and Arg2107His. Login to comment
180 One patient with Stargardt disease bore Leu541Pro without the Ala1038Val variant, and seven harbored the Ala1038Val change without Leu541Pro. Login to comment
181 Ala1038Val without Leu541Pro was also found in one patient with AMD. Login to comment
184 Considering only those variants predicted to cause protein truncation and missense changes compatible with disease association, we found 1 patient with five such variants, 11 with three, and a further 6 with two (Leu541Pro and Ala1038Val) that were on the same chromosome. Login to comment

PMID: 11379881 [PubMed] Yatsenko AN et al: "Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4)."

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61 Overall, these 33 mutant alleles represent 24 different ABCR alterations; 22 of 33 (66%) mutant alleles represent 15 different missense amino acid changes (one complex allele consisted of two missense mutations [L541P; A1038V]; Table 1, Fig.2). Login to comment
65 Allele 1 nucleotide Amino acid Allele 2 Amino acid Age of change nucleotide change onset (years) AR129-08 37 AR140-01 6079C→T L2027F 3322C→T R1108C 36 AR204-04 35 AR280-03 6316C→T R2106C 6710insA T2237fs 35 AR311-04 4462T→C C1488R 35 AR336-03 2588G→C G863A 5898+1G→A E1966splice 39 AR343-06 2588G→C G863A 3322C→T R1108C 43 AR387-03 4919G→A R1640Q 2971G→C G991R 40 AR410-04 768G→T V256splice 3113C→T A1038V 38 AR440-03 6238-6239del2 bp S2080fs 44 AR448-01a 454C→T R152X 6089G→A R2030Q 52 AR452-04 2005-2006del2 bp M669fs 6089G→A R2030Q 40 AR455-05 [1622T→C;3113C→T] [L541P;A1038V] 43 AR474-02 36 AR516-01a 5196+1G→A I1732splice 3113C→T A1038V 47 AR518-03 3322C→T R1108C 35 AR540-01a 4685T→C I1562T 51 AR594-02a 5196+1G→A I1732splice 36 AR606-04 3322C→T R1108C 2588G→C G863A 39 AR608-02 1025-1038del14 bp D342fs 40 AR617-03 2827C→T R943W 39 AR632-02a 3386G→T R1129L 50 AR649-03 3303G→A W1101X 3113C→T A1038V 36 AR662-02a 1015T→G W339G 50 AR723-01a 3602T→G L1201R 65 Fig.1 Pedigrees of late-onset Stargardt disease families (filled symbols STGD1-affected individuals). Login to comment
134 Conversely, missense mutations located in other regions (e.g., missense mutations in late-onset STGD1) might retain some ABCR activity. This hypothesis is supported by the observations of Sun et al. (2000) that ABCR missense mutations located outside the known functional domains (L541P, G863A, A1038V, R1108C, R1129L, C1488R, R2106C) have a milder functional effect on expression and ATP-binding activity (1/3-2/3 activity of wild-type). Login to comment

PMID: 10970771 [PubMed] Allikmets R et al: "Simple and complex ABCR: genetic predisposition to retinal disease."

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40 Second, both studies have identified a frequent, complex allele, L541P/A1038V, in patients of German origin who have both STGD and CRD (Maugeri et al. 2000 [in this issue]; Rivera et al. 2000 [in this issue]). Login to comment
46 In addition, the complexity of the genotype/phenotype-correlation studies in ABCR-related retinal dystrophies is underlined by the fact that two patients homozygous for the L541P/A1038V allele were diagnosed with CRD and STGD (Maugeri et al. 2000 [in this issue]; Rivera et al. 2000 [in this issue]). Login to comment
124 Last, both mutations found on the "German" complex allele, L541P and A1038V, even if analyzed separately, render the ABCR protein defective (Sun et al. 2000). Login to comment

PMID: 10958763 [PubMed] Rivera A et al: "A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration."

No. Sentence Comment

7 Eight different alleles account for 61% of the identified disease alleles, and at least one of these, the L541P-A1038V complex allele, appears to be a founder mutation in the German population. Login to comment
80 Nucleotide alterations occurring in sim- Table 2 ABCA4 Mutations Found in Patients with STGD and AMD and in Controls EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (288) AMD (400) Control (440) 3: 178GrA A60T 1 0 0 This study 179CrT A60E 1 0 0 This study 194GrA G65E 1 0 0 Fishman et al. (1999) 203CrT P68L 1 0 0 This study 214GrA G72R 1 0 0 This study 296insA Frameshift 2 0 0 This study 5: 454CrT R152X 1 0 0 This study 6: 634CrT R212C 1 0 0 Lewis et al. (1999) 688TrA C230S 1 0 0 This study 730delCT Frameshift 1 0 0 This study 740ArG N247S 1 0 0 This study 768GrT Splice 2 0 0 Maugeri et al. (1999) 8: 983ArT E328V 1a 0 0 This study 1086TrA Y362X 1 0 0 This study 10: 1317GrA W438X 1 0 0 This study 11: 1411GrA E471K 1 0 0 Lewis et al. (1999) 12: 1622TrC L541P 21a 1a 0 Rozet et al. (1998), Fishman et al. (1999), Lewis et al. (1999), Maugeri et al. (1999) 1715GrA R572Q 1a 0 0 Lewis et al. (1999) 13: 1819GrA G607R 1 0 0 This study 1903CrA Q635K 2a 0 0 This study 1903CrT Q635X 1 0 0 This study IVS13ϩ1GrA Splice 2 0 0 This study 14: 1957CrT R653C 1 0 0 This study 1988GrA W663X 1 0 0 This study 2041CrT R681X 4 0 0 Maugeri et al. (1999) 15: 2291GrA C764Y 1 0 0 This study 2292delT Frameshift 1a 0 0 This study 2295TrG S765R 1a 0 0 This study 16: 2564GrA W855X 1 0 0 Nasonkin et al. (1998) 17: 2588GrC Spliceb 17a 6 5 Allikmets et al. (1997a), Cremers et al. (1998), Lewis et al. (1999), Maugeri et al. (1999), Papaioannou et al. (2000) 18: 2701ArG T901A 0 2 0 This study 2741ArG H914A 0 0 1 This study 19: 2876CrT T959I 1 0 0 This study 20: IVS20ϩ5GrA Splice 1 0 0 This study 21: 3106GrA E1036K 1a 0 0 Nasonkin et al. (1998) 3113CrT A1038V 26a 4a 1 Allikmets et al. (1997a), Cremers et al. (1998), Rozet et al. (1998), Fishman et al. (1999), Lewis et al. (1999), Maugeri et al. (1999) T3187TrC S1063P 1 0 0 This study (Continued) 805 Table 2 Continued EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (288) AMD (400) Control (440) 22: 3292CrT R1097C 1 0 0 This study 3322CrT R1108C 4 0 0 Rozet et al. (1998), Fishman et al. (1999), Lewis et al. (1999) 24: 3528insTGCA Frameshift 1 0 0 This study 25: 3808GrT E1270X 1 0 0 This study 27: 3898CrT R1300X 1 0 0 This study 28: IVS28ϩ5GrA Splice 1 0 0 This study 4139CrT P1380L 1 0 0 Lewis et al. (1999) 4195GrA E1399K 2 0 0 This study 4234CrT Q1412X 4 0 0 Maugeri et al. (1999) 29: 4289TrC L1430P 2 0 0 This study 4318TrG F1440V 1 0 0 This study 4328GrA R1443H 1 0 0 This study 30: 4457CrT P1486L 1 0 0 Lewis et al. (1999) 4463GrA C1488Y 1 0 0 This study 31: 4610CrT T1537M 1 0 0 This study 35: IVS35ϩ2TrA Splice 1 0 0 This study 36: 5065TrC S1689P 1 0 0 This study 5114GrT R1705L 1 0 0 This study IVS36ϩ1GrA Splice 1 0 0 This study 37: 5198TrC M1733T 0 0 1 This study 5242GrA G1748R 1 0 0 This study 5248CrT Q1750X 1 0 0 This study 5288TrC L1763P 1 0 0 This study 38: IVS38ϩ1GrA Splice 1 0 0 This study 40: 5653GrA E1885K 1 0 0 This study 5693GrA R1898H 5 2 1 Allikmets et al. (1997b), Lewis et al. (1999) IVS40ϩ5GrA Splice 8a 0 0 Cremers et al. (1998), Lewis et al. (1999), Maugeri et al. (1999) 42: 5882GrA G1961E 34 4 2 Allikmets et al. (1997b), Fishman et al. (1999), Lewis et al. (1999), Maugeri et al. (1999) 43: 5917delG Frameshift 3 0 0 This study 5923GrC G1975R 1 0 0 This study 5929GrA G1977S 1 0 0 Rozet et al. (1998), Lewis et al. (1999) 45: 6229CrG R2077G 1 0 0 This study 6229CrT R2077W 1 0 0 Allikmets et al. (1997a), Fishman et al. (1999), Lewis et al. (1999) 48: 6609CrA Y2203X 2 0 0 This study 6647GrT A2216V 0 0 1 This study a Mutation pairs occurring on a single haplotype. Login to comment
90 In the group with AMD, 400 chromosomes were studied and 19 mutations were identified, with L541P and A1038V occurring on a single haplotype in one patient (AMD43). Login to comment
111 Likewise, for the intron 28 alteration, a spliced product Table 5 Patients with STGD Who Have Two Identified Disease Alleles AGE AT ONSET AND PATIENT MUTATION SEGREGATION IN FAMILY a Allele 1 Allele 2 5-9 years: STGD17 Q1412X R2077W Yes STGD88 G65E G1961E NA STGD93 G1961E G1961E Yes STGD99 L541P-A1038V G1961E Yes STGD100 L541P-A1038V IVS40ϩ5GrA Yes STGD108 Y362X IVS40ϩ5GrA Yes STGD109 L541P-A1038V W855X Yes STGD139b 5917delG 5917delG Yes STGD167 C1488Y IVS40ϩ5GrA Yes 10-14 years: STGD21 R681X R1898H NA STGD37 L541P-A1038V L541P-A1038V Yes STGD47/164 IVS13ϩ1GrA 2588GrC Yes STGD50 2588GrC A1038V NA STGD70 2588GrC IVS40ϩ5GrA NA STGD82 L541P-A1038V S1063P Yes STGD87 2588GrC Q1750X Yes STGD98 R212C T959I Yes STGD102 R572Q-2588GrC IVS35ϩ2TrA Yes STGD107 C764Y 3528ins4 Yes STGD120 L1430P L1430P NA STGD121 R1300X IVS40ϩ5GrA Yes STGD156 R1108C G1961E NA STGD159 R1108C Q1412X Yes STGD171 L541P-A1038V G1961E NA 15-19 years: STGD34 G768T G1961E Yes STGD39 L541P-A1038V R1443H NA STGD40/163 2588GrC E1885K Yes STGD45 E1399K G1977S Yes STGD59 R1898H G1975R NA STGD67 P68L S1689P Yes STGD75 Q635K IVS40ϩ5GrA Yes STGD111 2292delT-S765R G1961E Yes STGD114 Y2203X G1961E Yes STGD138 IVS13ϩ1GA 2588GrC Yes 20-24 years: STGD41 R681X G1961E Yes STGD63 A60T R1898H NA STGD86 296insA G1961E Yes STGD91 L541P-A1038V A1038V NA STGD113 L541P-A1038V 2588GrC Yes STGD118b IVS20ϩ5GrA G1961E Yes STGD119 L541P-A1038V G1961E Yes STGD122 L541P-A1038V G1961E Yes STGD135 W663X G1961E NA STGD147 IVS36ϩ1GrA G1961E Yes STGD168 L541P-A1038V G1961E NA 25-29 years: STGD62 G607R G1961E NA STGD71 296insA A1038V Yes STGD78 2588GrC Q1412X Yes STGD103 2588GrC IVS20ϩ5GrA Yes STGD116 L541P-A1038V G1961E Yes STGD139bb G1961E 5917delG Yes у30 years: STGD38 E471K G1961E Yes STGD68 E1399K G1961E Yes STGD69 L541P-A1038V 2588GrC NA STGD95 F1440V G1748R Yes STGD134 C230S G1961E NA STGD144 2588GrC R1705L NA STGD148 R1097C Y2203X NA STGD170 L541P-A1038V 2588GrC NA a NA p not applicable. Login to comment
149 Although the majority of mutations are rare, found in only one or two families, three disease alleles (2588GrC, L541P-A1038V, and G1961E) are present at high frequencies in the German population. Login to comment
152 The second-most-frequent allele is a complex allele, with A1038V occurring on the same haplotype as L541P (21/166 [12.7%]). Login to comment
153 Although the A1038V mutation is commonly reported in the literature, the L541P-A1038V complex allele has been reported only five times (Rozet et al. 1998; Fishman et al. 1999; Lewis et al. 1999; Maugeri et al. 1999). Login to comment
172 On the contrary, specific mutations are associated with highly variable ages at onset; for example, compound heterozygosity for the complex allele L541P-A1038V and G1961E was found in patients with age at onset of 9-25 years (table 5). Login to comment

PMID: 10958761 [PubMed] Maugeri A et al: "Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy."

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5 One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. Login to comment
32 Although the significance of this finding is under debate (Stone et al. 1998), at least two ABCA4 mutations (G1961E and D2177N) have been shown, in a large multicenter study, to be statistically more frequent in patients Table 1 ABCA4 Mutations in Patients with CRD PATIENT INHERITANCE ABCA4 ALLELE 1 ABCA4 ALLELE 2 Nucleotide Changes Effects Nucleotide Changes Effects 9250a Isolated 1622TrC;3113CrT L541P;A1038Vb 194GrA G65Eb 9303 AR 1622TrC;3113CrT L541P;A1038Vb 9336 Isolated 6658CrT Q2220X 9369a AR 6601-6602delAG Frameshift 9370 Isolated 1622TrC;3113CrT L541P;A1038Vb 9371 Isolated 1622TrC;3113CrT L541P;A1038Vb 1622TrC;3113CrT L541P;A1038Vb 9378a Isolated 768GrT 5 Splice mutationb 9553 AR 2588GrC DG863/G863Ab IVS35del-2rϩ2del4 3 Splice mutation 9633 Isolated 1622TrC;3113CrT L541P;A1038Vb 4469GrA C1490Yb 9650 Isolated 3364GrA E1122Kb 9887 Isolated 4793CrA A1598D 6329GrA W2110X 11872 Isolated 634CrT R212Cb 13163a AR 1622TrC;3113CrT L541P;A1038Vb IVS36ϩ1GrA 5 Splice mutationb a Patient with atypical CRD. Login to comment
60 In another patient (8547), there was only Figure 2 DNA sequences in patients carrying the complex ABCA4 allele L541P;A1038V. Login to comment
77 A complex L541P;A1038V allele was found in 7 of 19 mutant alleles. Login to comment
105 Seven alleles in six German patients with CRD were found to carry two missense mutations (L541P;A1038V). Login to comment
108 However, among a total of 357 non-German patients with STGD1, only 4 (1.1%) were shown to carry the L541P;A1038V allele (Rozet et al. 1998; Fishman et al. 1999; Lewis et al. 1999; Maugeri et al. 1999; Papaioannou et al. 2000; Simonelli et al. 2000). Login to comment

PMID: 10206579 [PubMed] Fishman GA et al: "Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene."

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70 Clinical Features of Patients With ABCR Gene Mutations* Patient No./ Sex/Age, y Clinical Phenotype Vision Silent Choroid Central Scotoma MutationOD OS 1/M/19 I 20/200 20/200 ND + Thr300Asn, exon 8 2/M/44 I 20/25 20/15 - + Cys1488Arg, exon 30 3/M/35 I 20/100 20/100 ND + Gly1961Glu, exon 42 Cys2150Tyr, exon 47 4/M/44 I 20/200 20/200 - + Gly1961Glu, exon 42 5/F/28 I 20/80 20/100 - + Gly1961Glu, exon 42 Gly65Glu, exon 3 6/M/36 I 20/25 20/200 - + Gly1961Glu, exon 42 Arg2077Trp, exon 45 7/F/44 I 20/200 20/200 - + Gly1961Glu, exon 42 8/M/41 I 20/200 20/200 - + Gly1961Glu, exon 42 9/F/32 I 20/25 20/30 - + Gly1961Glu, exon 42 10/F/36 I 20/50 20/200 - + Gly1961Glu, exon 42 11/M/31 I 20/200 20/200 - + Gly1961Glu, exon 42 Ala1038Val, exon 21 Leu541Pro, exon 12 12/M/35 I 20/200 20/200 - + Arg2107His, exon 46 Leu1729Pro, exon 36 13/M/22 II 20/200 20/200 + + 1bp del (g), codon 448, exon 10 14/F/9 II 20/200 20/40 ND + 9bp del, codon 1760/1761, exon 37 1bp ins (c), codon 1513, exon 30 15/M/19 II 10/120 10/160 + + 1bp ins (c), codon 1513, exon 30 Ala60Val, exon 3 16/M/25 II 20/200 20/200 + ND Ser974Pro, exon 20 17/F/12 II 20/200 20/200 ND + 2884 del (c), exon 19 18/F/73 II 20/30 20/25 + Paracentral scotoma 5bp del, codon 505, exon 11 19/F/35 II 10/160 10/120 ND + Val849Ala, exon 16 20/F/48 II 20/400 20/400 + +; Mild peripheral restriction Val849Ala, exon 16 Arg2107His, exon 46 21/M/54 II 20/200 20/200 + + Arg2030stop, exon 44 22/M/28 II 20/400 20/400 + + His2128Arg, exon 46 23/F/34 III 10/400 10/225 Diffuse hyperfluorescence ND Arg2038Trp, exon 44 24/F/53 III 10/700 10/600 Diffuse hyperfluorescence and notable choroidal atrophy + Arg1108Cys, exon 22 25/F/54 III 10/350 3/350 Diffuse hyperfluorescence +; Mild concentric restriction Tyr1652Asp, exon 35 Arg2107His, exon 46 26/M/57 III 20/50 20/80 ND ND Splice donor GϾA, exon 24 27/F/65 III 1/225 1/225 Diffuse choroidal atrophy Temporal islands Gly1961Glu, exon 42 frameshift del, codons 1620-1622, exon 35† 28/M/32 III 20/400 20/400 Diffuse hyperfluorescence +; Peripheral restriction Ala1038Val, exon 21 Leu541Pro, exon 12 Donor splice, exon 30 29/M/46 III 10/225 10/225 ND +; Peripheral restriction Trp1408Leu, exon 28 Ser206Arg, exon 6 Arg2107His, exon 46 *M indicates male; F, female; ND, angiography or visual field testing not done; +, present; and -, absent. Login to comment

PMID: 9973280 [PubMed] Lewis RA et al: "Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease."

No. Sentence Comment

76 2 0071GrA R24H 1 19 2894ArG N965S 3 36 5196ϩ1GrA Splice 2 3 0161GrA C54Y 1 21 3113CrT A1038V 16 5196ϩ2TrC Splice 1 0179CrT A60V 1 22 3211insGT FS 1 37 5281del9 PAL1761del 1 0203CrG P68R 1 3212CrT S1071L 1 38 5459GrC R1820P 1 0223TrG C75G 1 3215TrC V1072A 1 39 5512CrT H1838Y 1 6 0634CrT R212C 1 3259GrA E1087K 1 5527CrT R1843W 1 0664del13 FS 1 3322CrT R1108C 6 40 5585-1GrA Splice 1 0746ArG D249G 1 23 3364GrA E1122K 1 5657GrA G1886E 1 8 1007CrG S336C 1 3385GrT R1129C 1 5693GrA R1898H 4 1018TrG Y340D 1 3386GrT R1129L 2 5714ϩ5GrA Splice 8 11 1411GrA E471K 1 24 3602TrG L1201R 1 42 5882GrA G1961E 16 12 1569TrG D523E 1 25 3610GrA D1204N 1 5898ϩ1GrT Splice 3 1622TrC L541P 1 28 4139CrT P1380L 4 43 5908CrT L1970F 1 1715GrA R572Q 2 4216CrT H1406Y 1 5929GrA G1977S 1 1715GrC R572P 1 4222TrC W1408R 4 6005ϩ1GrT Splice 1 13 1804CrT R602W 1 4232insTATG FS 1 44 6079CrT L2027F 11 1822TrA F608I 2 4253ϩ5GrT Splice 1 6088CrT R2030X 1 1917CrA Y639X 1 29 4297GrA V1433I 1 6089GrA R2030Q 1 1933GrA D645N 1 4316GrA G1439D 2 6112CrT R2038W 1 14 2005delAT FS 1 4319TrC F1440S 1 45 6148GrC V2050L 2 2090GrA W697X 1 4346GrA W1449X 1 6166ArT K2056X 1 2160ϩ1GrC Splice 1 30a 4462TrC C1488R 2 6229CrT R2077W 1 16 2453GrA G818E 1 4457CrT P1486L 1 46 6286GrA E2096K 1 2461TrA W821R 1 30b 4469GrA C1490Y 3 6316CrT R2106C 1 2536GrC D846H 1 4539ϩ1GrT Splice 1 47 6391GrA E2131K 1 2552GrC G851D 1 31 4577CrT T1526M 7 6415CrT R2139W 1 17 2588GrC G863A 11 4594GrA D1532N 3 6445CrT R2149X 1 19 2791GrA V931M 2 35 4947delC FS 1 48 6543del36 1181del12 1 2827CrT R943W 1 36 5041del15 VVAIC1681del 2 6709insG FS 1 2884delC FS 1 5087GrA S1696N 1 NOTE.-FS ϭ frameshift. Login to comment
101 For the double-mutant chromosomes in the compound heterozygous families (AR31: Y340D and R572Q; AR106: E471K and E2131K; AR128: R572Q and G863A; and AR189: L541P and A1038V) and in those families in which the second disease chromosome was not identified (AR215: H1406Y and V2050L; AR264: D1204N and L2027F; AR254: D249G and R1898H; AR265: G863A and R1898H; AR285: 2714ϩ5GrA and 2884delC; and AR305: G863A and R1898H), in three cases (AR128, AR265, and AR305) each mutation on the double-mutant chromosome had been identified independently as disease causing in other, unrelated families with STGD1 (table 1). Login to comment
77 2 0071GrA R24H 1 19 2894ArG N965S 3 36 5196af9;1GrA Splice 2 3 0161GrA C54Y 1 21 3113CrT A1038V 16 5196af9;2TrC Splice 1 0179CrT A60V 1 22 3211insGT FS 1 37 5281del9 PAL1761del 1 0203CrG P68R 1 3212CrT S1071L 1 38 5459GrC R1820P 1 0223TrG C75G 1 3215TrC V1072A 1 39 5512CrT H1838Y 1 6 0634CrT R212C 1 3259GrA E1087K 1 5527CrT R1843W 1 0664del13 FS 1 3322CrT R1108C 6 40 5585afa;1GrA Splice 1 0746ArG D249G 1 23 3364GrA E1122K 1 5657GrA G1886E 1 8 1007CrG S336C 1 3385GrT R1129C 1 5693GrA R1898H 4 1018TrG Y340D 1 3386GrT R1129L 2 5714af9;5GrA Splice 8 11 1411GrA E471K 1 24 3602TrG L1201R 1 42 5882GrA G1961E 16 12 1569TrG D523E 1 25 3610GrA D1204N 1 5898af9;1GrT Splice 3 1622TrC L541P 1 28 4139CrT P1380L 4 43 5908CrT L1970F 1 1715GrA R572Q 2 4216CrT H1406Y 1 5929GrA G1977S 1 1715GrC R572P 1 4222TrC W1408R 4 6005af9;1GrT Splice 1 13 1804CrT R602W 1 4232insTATG FS 1 44 6079CrT L2027F 11 1822TrA F608I 2 4253af9;5GrT Splice 1 6088CrT R2030X 1 1917CrA Y639X 1 29 4297GrA V1433I 1 6089GrA R2030Q 1 1933GrA D645N 1 4316GrA G1439D 2 6112CrT R2038W 1 14 2005delAT FS 1 4319TrC F1440S 1 45 6148GrC V2050L 2 2090GrA W697X 1 4346GrA W1449X 1 6166ArT K2056X 1 2160af9;1GrC Splice 1 30a 4462TrC C1488R 2 6229CrT R2077W 1 16 2453GrA G818E 1 4457CrT P1486L 1 46 6286GrA E2096K 1 2461TrA W821R 1 30b 4469GrA C1490Y 3 6316CrT R2106C 1 2536GrC D846H 1 4539af9;1GrT Splice 1 47 6391GrA E2131K 1 2552GrC G851D 1 31 4577CrT T1526M 7 6415CrT R2139W 1 17 2588GrC G863A 11 4594GrA D1532N 3 6445CrT R2149X 1 19 2791GrA V931M 2 35 4947delC FS 1 48 6543del36 1181del12 1 2827CrT R943W 1 36 5041del15 VVAIC1681del 2 6709insG FS 1 2884delC FS 1 5087GrA S1696N 1 NOTE.-FS afd; frameshift. Login to comment
102 For the double-mutant chromosomes in the compound heterozygous families (AR31: Y340D and R572Q; AR106: E471K and E2131K; AR128: R572Q and G863A; and AR189: L541P and A1038V) and in those families in which the second disease chromosome was not identified (AR215: H1406Y and V2050L; AR264: D1204N and L2027F; AR254: D249G and R1898H; AR265: G863A and R1898H; AR285: 2714af9;5GrA and 2884delC; and AR305: G863A and R1898H), in three cases (AR128, AR265, and AR305) each mutation on the double-mutant chromosome had been identified independently as disease causing in other, unrelated families with STGD1 (table 1). Login to comment

PMID: 24509150 [PubMed] Serapinas D et al: "Stargardt disease caused by a rare combination of double homozygous mutations."

No. Sentence Comment

47 The analysis of the DNA testing results showed 2 mutations in the ABCA4 gene: a nucleotide substitution in exon 12 (c.1622T>C; L541P) and a nucleotide substitution in exon 21 (c.3113C>T; A1038V). Login to comment
60 Several studies have identified frequent ethnic group-specific ABCA4 alleles, such as the c.2588G>C variant resulting in a dual effect, p.G863A/delG863 as a founder mutation in Northern European patients with Stargardt disease, and a complex allele p.L541P/A1038V in the patients of the German origin who have both Stargardt disease and cone-rod dystrophy. Login to comment
64 Our presented mutations (L541P and A1038V) are not rare in Stargardt disease, but in this case, the disease was caused by a rare combination of double homozygous mutations. Login to comment
67 A1038V, a missense mutation, is reported as one of the most common mutations in the ABCA4 gene when is detected as a component of the complex allele L541P/A1038V. Login to comment
68 The complex allele demonstrates mislocalization and therefore reduced function of the ABCA4 protein, while the protein associated with A1038V alone does not mislocalize. Login to comment
69 A1038V is also pathogenic without L541P as it has a deleterious impact on ATPase by ABCA4 in vitro (13). Login to comment
46 The analysis of the DNA testing results showed 2 mutations in the ABCA4 gene: a nucleotide substitution in exon 12 (c.1622T>C; L541P) and a nucleotide substitution in exon 21 (c.3113C>T; A1038V). Login to comment
59 Several studies have identified frequent ethnic group-specific ABCA4 alleles, such as the c.2588G>C variant resulting in a dual effect, p.G863A/delG863 as a founder mutation in Northern European patients with Stargardt disease, and a complex allele p.L541P/A1038V in the patients of the German origin who have both Stargardt disease and cone-rod dystrophy. Login to comment
63 Our presented mutations (L541P and A1038V) are not rare in Stargardt disease, but in this case, the disease was caused by a rare combination of double homozygous mutations. Login to comment
66 A1038V, a missense mutation, is reported as one of the most common mutations in the ABCA4 gene when is detected as a component of the complex allele L541P/A1038V. Login to comment

PMID: 21510770 [PubMed] Burke TR et al: "Allelic and phenotypic heterogeneity in ABCA4 mutations."

No. Sentence Comment

7 The most common, L541P/A1038V, has been reported as a founder mutation in Hungaro-German populations.14,16,17 Furthermore "ethnic group-specific" ABCA4 alleles have been described in other populations also, C1490Y and R602W in South African patients,18 and N965S in a Danish population19 among others.20 In an attempt to explain the variability seen in ABCA4 retinal phenotypes and to correlate this with individual mutation effect, a model was proposed which correlated disease severity with residual ABCA4 function.14,21 Maugeri classified ABCA4 mutant alleles as "mild", "moderate", and "severe" based on the predicted effect of the mutation on the transport function of the protein, ie, the more severe the effect of the mutation on ABCA4 function, the more aggressive the disease phenotype. Login to comment

PMID: 21911583 [PubMed] Zernant J et al: "Analysis of the ABCA4 gene by next-generation sequencing."

No. Sentence Comment

17 Several studies have identified frequent "ethnic group-specific" ABCA4 alleles, such as the c.2588Gb0e;C variant resulting in a dual effect, p.G863A/delG863, as a founder mutation in Northern European patients with STGD17 and a complex allele (two variants on the same chromosome), p.L541P/A1038V, in both STGD1 and CRD patients of German origin (Fig. 2B).3,8 Complex ABCA4 alleles are not uncommon in STGD1.9 In fact, they are detected in approximately 10% of all STGD patients.10 Allelic heterogeneity has substantially complicated genetic analyses of ABCA4-associated retinal disease. Login to comment
66 (B) An example of a pedigree segregating a frequent complex ABCA4 allele [c.1622Tb0e;C; 3113Cb0e;T] (p.L541P;A1038V), in which either mutation separately can cause the disease. Login to comment
145 The best known example from this category in ABCA4 is the c.5461-10Tb0e;C variant in intron 38, which is the third most frequent variant (found in 7.1% of STGD1 patients) after the p.G1961E and p.L541P/A1038V mutations in our study. Login to comment

PMID: 23755871 [PubMed] Riveiro-Alvarez R et al: "Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families."

No. Sentence Comment

88 Based on our data, the likely severe ABCA4 missense mutations, resulting in an early disease onset and severe disease, include, among others: p.Leu541Pro, p.Arg602Trp, p.Thr1019Met, p.Leu1940Pro, and p.His1838Asp. Login to comment
90 These results are supported by previous findings that the p.Leu541Pro and p.Arg602Trp variants result in mislocalized protein,22 the p.Leu1940Pro and IVS38e10T/C variants confer much earlier onset of the disease,23 and the p.His1838Asp variant, in a complex allele with the p.Gly1961Glu mutation, results in an early-onset, severe disease.24 Although the above estimates are simplified because they do not take into account environmental factors and genetic variation at other loci in these patients, they serve as a good basis for association with disease onset and disease severity. Login to comment

PMID: 23769331 [PubMed] Fujinami K et al: "The clinical effect of homozygous ABCA4 alleles in 18 patients."

No. Sentence Comment

7 Results: Eleven disease-associated homozygous ABCA4 alleles were identified, including 1 frame shift, 2 stops, 1 intronic variant causing splice-site alteration, 2 complex missense variants, and 5 missense variants: p.Glu905fsX916, p.Arg1300X, p.Gln2220X, c.4253&#fe;4 C>T, p.Leu541Pro and p.Ala1038Val (homozygosity for complex allele), p.Val931Met and p.Arg1705Gln (complex allele), p.Arg212Cys, p.Cys1488Arg, p.Arg1640Trp, p.Gly1961Glu, and p.Leu2027Phe. Login to comment
10 Two patients with homozygous missense variants (p.Leu541Pro and p.Ala1038Val [complex], and p.Arg1640Trp) presented with a severe phenotype. Login to comment
60 Sex Ethnicity Consanguinity Age at Onset (yrs) Age (yrs) Duration of Disease (yrs) LogMAR VA Fundus Appearance AF Pattern ERG Group OCT Central Foveal Thickness (mm) Mutation Status RE LE RE LE 1 1 M S Asian Yes (1st cousin) 11 33 22 1.0 1.0 2 2 1 64 69 c.634 C>T, p.Arg212Cys 2 1 F S Asian Yes (1st cousin) 11 36 25 1.0 1.0 2 2 3 31 41 c.634 C>T, p.Arg212Cys 3* 2 M European No 3 8 5 1.2 1.2 2 2 3y 41 36 c.1622 T>C, p.Leu541Pro / c.3113 C>T, p.Ala1038Val 4 3 F S Asian Yes (2nd cousin once removed) 5 8 3 1.0 1.0 2 2 3 NA NA c.2713delG, p.Glu905fsX916 5 4 M S Asian Yes (unknown) 10 25 15 1.0 1.08 2 2 3 64 60 c.2791 G>A, p.Val931Met / c.5114 G>A, p.Arg1705Gln 6 5 M S Asian Yes (1st cousin) 10 30 20 1.0 1.0 2 2 3 NA NA c.4462 T>C, p.Cys1488Arg 7 5 F S Asian Yes (1st cousin) 10 22 12 2.0 1.0 2 2 3 NA NA c.4462 T>C, p.Cys1488Arg 8 6 M ME Asian Yes (1st cousin) 30 36 6 1.08 2.0 3 3 3 103 95 c.4918 C>T, p.Arg1640Trp 9 7 F S Asian Yes (2nd cousin) 19 27 8 1.78 2.0 1 2 1 128 90 c.5882 G>A, p.Gly1961Glu 10 7 M S Asian Yes (2nd cousin) 30 34 4 0.48 0.48 1 2 1 NA NA c.5882 G>A, p.Gly1961Glu 11 8 F S Asian Yes (1st cousin) 17 26 9 0.78 0.78 1 1 1 54 47 c.5882 G>A, p.Gly1961Glu 12 9 F European No 44 44 0 0.18 0.0 2 2 1 NA NA c.6079 C>T, p.Leu2027Phe 13 10 M ME Asian Yes (1st cousin) 5 11 6 1.3 1.0 3 2 3 62 68 c.3898 C>T, p.Arg1300X 14 11 M S Asian Yes (unknown) 8 11 3 1.0 1.0 2 2 3 NA NA c.4253&#fe;4 C>T 15 12 M S Asian Yes (1st cousin) 9 48 39 3.0 3.0 3 NA 3 NA NA c.6658 C>T, p.Gln2220X 16 13 M S Asian Yes (uncle and niece) 4 7 3 1.08 1.08 1 NA 3 NA NA c.6658 C>T, p.Gln2220X 17 13 M S Asian Yes (uncle and niece) 6 8 2 1.08 1.0 1 NA 3 NA NA c.6658 C>T, p.Gln2220X 18 13 M S Asian Yes (1st cousin) 17 25 8 1.78 1.78 3 NA 3 NA NA c.6658 C>T, p.Gln2220X AF &#bc; autofluorescence; ERG &#bc; electroretinography; F &#bc; female; FM No. Login to comment
100 Patient 3, homozygous for both p.Leu541Pro and p.Ala1038Val, showed a very severe phenotype: age of onset (3 years), visual acuity (1.2 for both eyes), type 2 fundus appearance, type 2 AF pattern, and ERG group 3. Login to comment
120 Patient 3, homozygous for p.Leu541Pro and p.Ala1038Val, had a very early onset associated with severe disease. Login to comment
125 In conclusion, 2 patients were homozygous for 2 variants previously reported as associated with disease (patient 3, p.Leu541Pro and p.Ala1038Val; patient 5, p.Val931Met and p.Arg1705Gln; Table 4, available at http://aaojournal.org). Login to comment

PMID: 23882696 [PubMed] Ritter M et al: "Characterization of stargardt disease using polarization-sensitive optical coherence tomography and fundus autofluorescence imaging."

No. Sentence Comment

143 [1622T>C; 3113C>T] (p.[Leu541Pro; Ala1038Val]), which is generally considered to be associated with more severe disease progression.40 Patient 12 carried this allele together with the same novel missense mutation (p.Glu955Gly) on the second chromosome as his younger sister (patient 10, STGD phenotype 2), which is suggestive of intrafamilial phenotype variation associated with this specific combination of ABCA4 mutations. Login to comment
198 [1622T>C; 3113C>T p.[Leu541Pro; Ala1038Val]), respectively. Login to comment
202 On the other hand, STGD phenotype 2 was associated with the presence of the known severe complex mutation Leu541Pro/ Ala10398Val in two of four cases, while three of four patients within phenotype 3 carried this mutation. Login to comment

PMID: 23953153 [PubMed] Fujinami K et al: "Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function."

No. Sentence Comment

45 Mutation screening of ABCA4 was performed with the arrayed primer extension (APEX) microarray (ABCR400 chip, Asper Ophthalmics, TABLE 1. Summary of Clinical Findings and Molecular Status of 40 Patients With a Foveal-Sparing Phenotypea of Stargardt Disease Patient Onsetb (y) Age (y) LogMAR Visual Acuity Fundus Patternc OCT ERGe Mutation Status CFTd (mm) ORT Group PERG mfERG OD OS OD OS OD OS OD OS 1 45 45 0 0 3 219 223 NA NA NA NA NA [c.1411 G>A, p.Glu471Lys/c.2588 G>C, p. Gly863Ala/c.4594 G>A, p.Asp1532Asn/c.5693 G>A, p.Arg1898His] 2 33 33 0.18 0.48 1 NA NA 3 ND ND NA NA [c.1622 T>C, p.Leu541Pro/c.3113 C>T, p.Ala1038Val/c.6089 G>A, p.Arg2030Gln] 3 53 66 0.18 0.18 1 NA NA 2 A A NA NA [c.768 G>T, Splice site/c. 6320 G>A, p. Arg2107His ] 4 37 54 1.48 0.18 1 32 39 U 3 ND ND 2 2 [c.1760 &#fe;1 G>T, Splice site/c.4594 G>T, p.Asg1532Tyr ] 5 57 57 0.3 0.18 1 NA NA 1 ND ND NA NA [c. Login to comment
126 Index (0-1) Pred. Hum Var Score (0-1) Site Affected Wt CV Mt CV CV % Variation 2 c.71G>A, p.Arg24His 1 Het Lewis48 Tol. NA PRD 0.98 No change ND 6 c.768G>T, Splice site 1 Het Klevering20 Tol. 0.56 NA Donor 70.4 58 Site broken (17.51) ND 6 c.658C>T, p.Arg220Cys 1 Het Webster53 Tol. NA Benign 0.39 No change ND 11 c.1411G>A, p.Glu471Lys 1 Het Allikmets46 Tol NA Benign 0.01 Acceptor 71.7 43 Site broken (40.4) 11/13006 db SNP (rs1800548) 12 c.1622T>C, p.Leu541Pro 1 Het Fishman8 Intol. 0.00 PRD 0.961 No change 2/13006 db SNP (rs61751392) Int 12 c.1760&#fe;1G>T, Splice site 1 Het This study NA NA Donor 84.6 58 WT site broken (31.72) ND 13 c.1805G>A, p.Arg602Gln 2 Het Webster53 Tol. NA PRD 0.513 48.9 78 New site (&#fe;59.14) 2/13006 db SNP (rs61749410) 14 c.1957C>T, p.Arg653Cys 2 Het Rivera49 Tol. 0.10 PRD 0.999 No change ND 17 c. Login to comment
141 Allele Frequencies of 72 ABCA4 Variants Identified in a Comparison Groupa With the Typical Stargardt Disease (140 Patients Without Evidence of Foveal Sparing on Autofluorescence Imaging) Exon Nucleotide Substitution and Amino Acid Change Number of Alleles Allele Frequency 2 c.71G>A, p.Arg24His 1 0.36% 2 c.161G>A, p.Cys54Tyr 3 1.07% 3 c.223T>G, p.Cys75Gly 1 0.36% 5 c.455G>A, p.Arg152Gln 1 0.36% 5 c.454C>T, p.Arg152* 1 0.36% 5 c.466 A>G, p.Ile156Val 2 0.71% 6 c.634C>T, p. Arg212Cys 3 1.07% 6 c.656G>C, p.Arg219Thr 1 0.36% 6 c.666_678delAAAGACGGTGCGC, p.Lys223_Arg226delfs 2 0.71% 6 c.768G>T, Splicing site 4 1.42% 8 c.1037A>C, p.Lys346Thr 1 0.36% 10 c.1222C>T, p.Arg408* 3 1.07% 12 c.1622T>C, p.Leu541Pro 2 0.71% 12 c.1648 G>T, p.Gly550* 1 0.36% 13 c.1804C>T, p.Arg602Trp 1 0.36% 13 c.1817G>A, p.Gly606Asp 1 0.36% 13 c.1922G>C, p.Cys641Ser 1 0.36% Int 13 c.1937&#fe;1G>A, Splicing site 2 0.71% 14 c.1957C>T, p.Arg653Cys 2 0.71% 17 c.2588G>C, p.Gly863Ala 19 6.79% 18 c.2701A>G, p.Thr901Ala 1 0.36% 19 c.2791G>A, p.Val931Met 2 0.71% 19 c.2894A>G, p.Asn965Ser 1 0.36% 20 c.2966T>C, p.Vla989Ala 3 1.07% 20 c.2971G>C, p.Gly991Arg 2 0.71% 21 c.3056C>T, p.Thr1019Met 1 0.36% 21 c.3113C>T, p.Ala1038Val 3 1.07% 21 c.3064G>A, p.Glu1022Lys 2 0.71% 22 c.3211_3212insGT, p.Ser1071Cysfs 6 2.14% 22 c.3259G>A, p.Glu1087Lys 4 1.43% 22 c.3292C>T, p.Arg1098Cys 1 0.36% 22 c.3322C>T, p.Arg1108Cys 5 1.79% 22 c.3323G>A, p.Arg1108His 1 0.36% 23 c.3364G>A, p.Glu1122Lys 1 0.36% 23 c.3386G>A, p.Arg1129His 1 0.36% 24 c.3602T>G, p.Leu1201Arg 3 1.07% 27 c.3898C>T, p.Arg1300* 2 0.71% 28 c.4139C>T, p.Pro1380Leu 14 5.00% 28 c.4222T>C, p.Trp1408Arg 1 0.36% 28 c.4234C>T, p.Gly1412* 1 0.36% 28 c.4253&#fe;5G>T, Splice site 1 0.36% 28 c.4253&#fe;4C>T, Splice site 1 0.36% 29 c.4283C>T, p.Thr1428Met 1 0.36% 29 c.4319T>C, p.Phe1440Ser 1 0.36% 29 c.4462T>C, p.Cys1488Arg 1 0.36% 30 c.4469G>A, p.Cys1490Tyr 5 1.79% 30 c.4537_4538insC, p.Gly1513Profs 1 0.36% 31 c.4577C>T, p.Thr1526Met 2 0.71% 33 c.4715C>T, p.Thr1572Met 1 0.36% Continued on next page TABLE 3. Login to comment

PMID: 24011517 [PubMed] Utz VM et al: "Identification of three ABCA4 sequence variations exclusive to African American patients in a cohort of patients with Stargardt disease."

No. Sentence Comment

121 Population-Specific ABCA4 Alleles in Patients with Stargardt Disease References Population Allele Protein Rivera et al.28 Hargitai et al.12 Hungaro-German c.1622T>C/c.3113C>T p.L541P/p.A1038V September et al.47 Afrikaner c.4469G>A p.C1490Y September et al.47 Afrikaner c.1804C>T p.R602W Rosenberg et al.48 Danish c.2894A>G p.N965S Maugeri et al.27 Western European c.2588G>C p.G863A Maia-Lopes et al.49 Portuguese c.32T>C p.L11P Valverde et al.29 Spanish c.5882G>A p.R1129L Fumagalli et al.50 Italian c.2099G>A p.W700X VOL. 156, NO. 6 ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST, and the following were reported. Login to comment

PMID: 24071957 [PubMed] Duncker T et al: "Distinct characteristics of inferonasal fundus autofluorescence patterns in stargardt disease and retinitis pigmentosa."

No. Sentence Comment

51 Summary of Demographic, Clinical, and Genetic Data Patient Condition ABCA4 Mutations Sex Age, y Eye Iris Color Race/Ethnicity BCVA Snellen (logMAR) P1 STGD1 p.P1380L, p.G1961E M 12 OS Blue White 20/100 (0.70) P2 STGD1 p.P1380L, p.G1961E F 17 OS Brown White 20/150 (0.88) P3 STGD1 p.Q1003X, p.G1961E M 25 OS Brown White 20/40 (0.30) P4 STGD1 p.C54Y F 48 OD Blue White 20/30 (0.20) P5 STGD1 p.R2077W F 52 OD Blue White 20/40 (0.30) P6 STGD1 p.[L541P;A1038V] M 13 OS Brown White 20/150 (0.88) P7 STGD1 p.T972N, p.L2027F F 14 OS Blue White 20/80 (0.60) P8 STGD1 c.4537_4538insC, p.V1686M M 49 OS Brown White 20/50 (0.40) P9 STGD1 p.R1108H, p.P1380L M 50 OS Blue White 20/200 (1.00) P10 STGD1 c.5714&#fe;5G>A F 34 OD Blue White 20/200 (1.00) P11 STGD1 p.Q636H, p.G1961E M 46 OD Brown Indian 20/400 (1.30) P12 STGD1 c.5461-10T>C M 35 OD Brown Black 20/400 (1.30) P13 STGD1 p.R1640W F 20 OD Brown Black 20/125 (0.80) P14 STGD1 p.R290W M 47 OS Brown White 20/40 (0.30) P15 STGD1 p.A1773V, p.G1961E M 18 OD Brown White 20/150 (0.88) P16 AD RP p.T17M* F 23 OD Brown Hispanic 20/30 (0.20) P17 AD RP N/A M 39 OS Brown White 20/20 (0.00) P18 AR RP N/A M 50 OS Green White 20/20 (0.00) AD, autosomal dominant; AR, autosomal recessive; BCVA, best corrected visual acuity; F, female; logMAR, logarithm of the minimum angle of resolution; M, male; N/A, not available. Login to comment

PMID: 24453473 [PubMed] Kjellstrom U et al: "Association between genotype and phenotype in families with mutations in the ABCA4 gene."

No. Sentence Comment

199 The c3113 C>T mutation has previously most often been described as a component of the complex allele c1622 T>C;c3113 C>T (L541P/A;A1038V) [11,25,38], but it is also known to be pathogenic as a separate mutation [15,40]. Login to comment

PMID: 24550365 [PubMed] Huang WC et al: "Inner and outer retinal changes in retinal degenerations associated with ABCA4 mutations."

No. Sentence Comment

74 Characteristics of the ABCA4-Related Retinal Disease Patients Patient Age at Visits, y Sex Allele 1 Allele 2 Previous Report*ߤ P1 9, 12 M E341G F608I P2 9, 15 M R681X C2150Y P28* P3ߥ 12 M N965S W821R P1ߤ P4 13, 16 M V256V T1526M P21*, P15ߤ P5 14, 20 F W1408R IVS40&#fe;5 G>A P49* P6ߥ 16 F V989A IVS28&#fe;5 G>T P17ߤ P7ߥ 16 M N965S W821R P18ߤ P8 18, 20 F Y362X IVS38-10 T>C P9ߥ 18 F V989A IVS28&#fe;5 G>T P10 18, 22 M G1961E R1129L P3ߤ P11 20 M R1640Q c.5174_5175insG P12ߥ 20 M G1961E G1961E/P68L P13 22, 25 M G863A IVS35&#fe;2 T>C P20ߤ P14 22, 24 F G1961E R152X P12*, P21ߤ P15ߥ 23 M G1961E G1961E/P68L P16 25, 27 M G1961E R152X P11* P17 26, 32 F L1940P R1129L P64* P18 27, 34 F R1925G A1038V/L541P P19 27, 29 M c.4530_4531insC R1705Q P52*, P5ߤ P20 28, 30 F G1961E A1038V/L541P P23ߤ P21 31, 35 M T1019M G1961E P34* P22ߥ 32, 37 M P1486L Deletion of exon 7 P25ߤ P23 33, 35 M G863A R1108C P29*, P6ߤ P24 34, 37 F IVS40&#fe;5 G>A V935A P32*, P7ߤ P25 34 M G1961E &#a7; P8ߤ P26 37, 43 F C54Y G863A P4* P27 39, 44 F G863A C1490Y P30*, P26ߤ P28 40 M G1961E C54Y P7*, P10ߤ P29 41 F IVS38-10 T>C E1087D P59* P30ߥ 43, 47 F G1961E V256V P23*, P11ߤ P31ߥ 47, 51 F P1486L Deletion of exon 7 P32 47 M Y245X Y245X P20* P33ߥ 48, 51 F G1961E V256V P22*, P12ߤ P34 48, 50 F c.3208_3209insTG IVS40&#fe;5 G>A P35 50, 54 M V1433I L2027F P50* P36ߥ 52, 55 F T1526M R2030Q P55*, P28ߤ P37 53, 59 F G1961E P1380L P47*, P13ߤ P38ߥ 53, 61 M L1940P IVS40&#fe;5 G>A P61* P39 58 M D600E R18W P2*, P14ߤ P40 59, 62 M E1122K G1961E P44* P41 59, 62 F R1640Q G1961E P58* P42ߥ 62 F T1526M R2030Q P54* P43ߥ 64, 68 M L1940P IVS40&#fe;5 G>A P62* P44 68 F R1108C IVS40&#fe;5 G>A P42* P45 71 F IVS38-10 T>C &#a7; Novel variants are bold and italicized. Login to comment

PMID: 24677105 [PubMed] Burke TR et al: "Quantitative fundus autofluorescence in recessive Stargardt disease."

No. Sentence Comment

47 In some cases where no mutations were detected by the array, or in more recently recruited patients, the next generation sequencing of the entire ABCA4 open reading frame and adjacent intronic sequences was performed on the Roche 454 platform.30 The four most common mutations found in six or more patients were: G1961E (12 patients from 11 families); L541P/ A1038V (eight patients from five families); L2027F (six patients from five families); and P1380L (six patients from six families). Login to comment
49 For the purposes of analyses reported below, we will refer to those eight mutations as the ''more common mutations.`` In two patients (two families), A1038V was present in a compound heterozygous state with other mutations while not as a complex allele with L541P (Table 1). Login to comment
77 [L541P; A1038V] 639 627 1.9 2.0 1.2 M 7 1 0.30 0.18 - I p. Login to comment
78 [L541P; A1038V] 413 1.9 2 F 25 11 0.80 0.80 II II p.G863A; c.5898&#fe;1G > A 710 675 3.4 3.3 3 M 11 6 0.80 0.70 I - p.G1961E; p.P1380L 267 2.3 4.1 M 35 10 0.30 0.18 I - p.G1961E; p. Login to comment
79 [L541P; A1038V] 426 2.1 4.2 M 35 10 0.40 0.48 I I p.G1961E; p. Login to comment
80 [L541P; A1038V] 356 354 1.7 1.8 5 F 14 1 0.60 0.60 II II p.L2027F; p.T972N 737 718 2.3 2.6 6 M 45 31 1.00 0.88 I I p.G1961E; p.P1380L 623 543 4.2 4.0 7 F 42 5 0.30 CF - I p.E1252* 557 2.1 8 M 15 4 0.80 0.80 II II p.L2027F; p.R2077W 728 697 3.2 3.2 9 F 24 2 0.60 0.40 II II p.R1161S 571 647 3.8 3.5 10 M 46 15 1.30 1.30 I I p.G1961E; p.Q636H 394 351 2.3 2.4 11.1 M 12 2 1.00 1.00 II - p. Login to comment
81 [L541P; A1038V]; p.R1640W 911 3.3 11.2 F 10 4 1.00 1.00 II - p. Login to comment
82 [L541P; A1038V]; p.R1640W 850 4.4 12 F 27 9 1.30 1.00 - III p.P1380L; p.P1380L 577 4.8 13 F 39 8 0.12 0.00 - I c.250_251insCAAA 616 2.3 14 M 23 4 0.88 0.60 - II p.C54Y 535 5.1 15.1 M 49 17 1.00 0.88 I I p.Y1557C 646 604 4.1 3.9 15.2 M 46 7 0.10 0.48 I I p.Y1557C 456 508 2.6 2.3 16.1 F 27 14 0.88 0.88 III III p.L2027F; p.G851D 448 459 6.0 6.3 16.2 F 29 19 1.30 1.18 III III p.L2027F; p.G851D 538 569 7.4 7.9 17 M 22 18 1.30 1.00 III III p.P1380L; p.R2030Q 434 411 5.7 6.0 18 M 37 16 0.70 0.70 I I p.G1961E; p.G1961E 281 279 2.6 2.2 19 F 33 5 0.88 0.70 I I p.G1961E; c.4540-2A > G 412 420 2.5 2.8 20 F 26 12 0.60 0.60 - I p.G1961E; p. Login to comment
83 [L541P; A1038V] 398 2.4 21 F 45 31 0.88 0.88 I I p.R1640W 647 613 2.6 2.8 22 M 43 7 1.00 0.00 - III p.A1773V; p.G1591G 640 6.9 23 F 41 1 0.10 CF II II p.P1486L; p.A1598D 613 572 6.0 6.5 24 F 19 4 0.60 0.70 I - p.G1961E; p.P1380L 368 2.4 25 F 23 4 0.88 0.80 - I p. Login to comment
85 [L541P; A1038V]; p.L2027F 733 749 3.9 4.0 36 F 20 7 0.88 1.00 II II p.R1640W 571 552 3.4 3.8 37 F 12 3 0.80 0.80 I I p.R1108C; p.Q1412* 536 501 1.7 1.7 * All subjects were white, except for patients 10, 22, and 36 who were Indian, Hispanic, and black, respectively. Login to comment
135 Comparing each of the four most common mutations separately with healthy eyes, G1961E (P &#bc; 0.001); L541P/ A1038V (P < 0.001); L2027F (P < 0.001); and P1380L (P &#bc; 0.024) eyes had qAF8 that was significantly higher than in FIGURE 2. Login to comment
146 When corrected for age (P &#bc; 0.04) and sex (P &#bc; 0.004), compared with all other patients who did not have that particular mutation, the mutations L2027F (P &#bc; 0.009) and L541P/A1038V (P &#bc; 0.015) were associated with higher qAF8, while A1038V (when not in conjunction with L541P, P &#bc; 0.06); G851D (P &#bc; 0.006); and G1961E (P < 0.001) were associated with lower qAF8 in this sample. Login to comment
152 Genotype-Phenotype Relations (TF) When compared separately with healthy eyes, three of the four most common mutations, L541P/A1038V (P < 0.001); L2027F (P < 0.001); and P1380L (P &#bc; 0.001), had TF that was significantly higher than in healthy eyes, when corrected for age. Login to comment
180 The mutations were confirmed in six or more patients (G1961E, L541P/A1038V, L2027F, and P1380L) or in two to four patients (R1640W, Y1557C, G851D, and R2030Q). Login to comment
181 Also shown is mutation A1038V in a compound heterozygous state with other mutations while not as a complex allele with L541P. Login to comment
226 For example, based on our cross-sectional data, the mutations L2027F and L541P/A1038V seem to confer a faster rate of accumulation, whereas G1961E and G851D seems to confer a slower increase (Fig. 5). Login to comment
227 The complex allele L541P/A1038V involves missense mutations in both the exocytoplasmic domain-1 and nucleotide FIGURE 7. Login to comment
230 binding domain (NBD)-1 and confers severe STGD1 with relatively early onset of retina-wide disease.44-47 In our study, the L541P/A1038V complex allele was in some patients associated with high qAF8 even at young ages, while in other patients, particularly in those compound heterozygous for L541P/A1038V and G1961E, qAF8 values were relatively lower (Fig. 5). Login to comment
232 Thus it is likely that in these cases, the lower qAF values do not reflect a decrease in qAF after an earlier rapid elevation, but rather a slower increase in qAF8 due to the presence of the G1961E allele (L541P/A1038V &#fe; G1961E). Login to comment

PMID: 24713488 [PubMed] Bertelsen M et al: "Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies."

No. Sentence Comment

89 mutation (21%), p.G863A, c.2408delG, and p.L541P/A1038V. Login to comment
123 Summary of Detected Potential Pathogenic Variants (Known and Novel [in Bold Face]) Found in the ABCA4 Gene of Patients With Generalized Choriocapillaris Dystrophy Patient Method Mutation 1 Mutation 2 Nucleotide Protein Nucleotide Protein D513 NGS c.203C>T p.P68L c.2894A>G p.N965S D514 Microarray, NGS c.2894A>G p.N965S c.5461-10T>C - D516 NGS c.4926C>G p.S1642R c.5041_5055del p.V1681_C1685del D517 NGS c.5169C>G p.Y1723* c.6079C>T p.L2027F D137 Microarray, NGS c.2894A>G p.N965S c.2894A>G p.N965S D801 Microarray, NGS c.6386&#fe;1G>A Aberrant splicing c.4234C>T p.Q1412* D109 Microarray c.2894A>G p.N965S c.4234C>T p.Q1412* D040 Microarray c.6229C>T p.R2077W c.6229C>T p.R2077W D159 Microarray c.3113C>T p.L541P/A1038V c.3113C>T p.L541P/A1038V D129 Microarray c.2894A>G p.N965S c.3322C>T p.R1108C D115 Microarray c.2894A>G p.N965S c.3113C>T p.L541P/A1038V D033 Microarray c.2894A>G p.N965S c.2041C>T p.R681* D023 Microarray c.203C>T p.P68L c.3329-2A>G Aberrant splicing D001 Microarray c.666_678del p.K223_R226delfs c.4667&#fe;2T>C Aberrant splicing D147 Microarray, HRM c.2894A>G p.N965S c.2408delG p.G803fs D162 Microarray c.3329-2A>G Aberrant splicing c.6089G>A p.R2030Q D022 Microarray, HRM c.4462T>C p.C1488R c.4102C>T p.R1368C D112 Microarray, HRM c.2894A>G p.N965S c.1529T>G p.L510R D108 Microarray, HRM c.1648G>A p.G550R c.4102C>T p.R1368C D107 Microarray c.666_678del p.K223_R226delfs c.2588G>C p.G863A D070 Microarray c.2588G>C p.G863A c.2588G>C p.G863A D116 Microarray c.2300T>A p.V767D c.5461-10T>C - D135 Microarray, HRM c.2894A>G p.N965S c.2408delG p.G803fs D117 Microarray, HRM c.3191-2A>G Aberrant splicing c.2408delG p.G803fs D186 Microarray, HRM c.3322C>T p.R1108C c.6386&#fe;1G>A Aberrant splicing D173 Microarray, HRM c.4469G>A p.C1490Y c.2915C>A p.T972N TABLE 3. Login to comment
124 In Silico Analysis of ABCA4 Variants Detected in This Study Using Alamut 2.2 Software cDNA Variant Protein Variant Effect on Protein Function AGVGD Class SIFT Prediction Effect on Protein PPH2 Prediction Effect on Protein TASTER Prediction Effect on Splicing Missense variants c.203C>T p.P68L C65 Deleterious Probably damaging Disease causing c.1529T>G p.L510R C65 Deleterious Benign Polymorphism c.1622T>C p.L541P Reduced ATP binding mislocali- zation26,27 C65 Deleterious Probably damaging Disease causing c.1648G>A p.G550R C65 Deleterious Possibly damaging Disease causing New acceptor site c.2300T>A p.V767D Reduced protein28 C65 Deleterious Benign Disease causing c.2588G>C p.G863A Reduced protein level, reduced ATP binding, reduced ATPase activity26 C55 Deleterious Possibly damaging Disease causing Predicted change at acceptor site 1 bp upstream: 11.1%, creating a new stronger acceptor 3 bp downstream c.2894A>G p.N965S Reduced ATP binding26 C45 Deleterious Probably damaging Disease causing New acceptor site c.2915C>A p.T972N C55 Deleterious Probably damaging Disease causing c.3113C>T p.A1038V Reduced ATP binding, reduced ATP hydrolysis26 C65 Deleterious Benign Disease causing c.3322C>T p.R1108C Reduced ATP binding26 C65 Deleterious Probably damaging Disease causing c.4102C>T p.R1368C C65 Deleterious Probably damaging Disease causing c.4462T>C p.C1488R C65 Deleterious Possibly damaging Disease causing c.4469G>A p.C1490Y Misfolding, mislocali- zation27 C65 Deleterious Probably damaging Disease causing Cryptic donor strongly activated c.4926C>G p.S1642R C25 Deleterious Benign Disease causing c.6079C>T p.L2027F Reduced ATP binding26,29 C15 Deleterious Probably damaging Disease causing c.6089G>A p.R2030Q C35 Deleterious Probably damaging Disease causing c.6229C>T p.R2077W Reduced ATP binding26 C65 Deleterious Probably damaging Disease causing Deletion/frame-shift/stop variants c.666_678del p.K223_ R226delfs c.2041C>T p.R681* c.2408delG p.G803fs c.4234C>T p.Q1412* c.5041_5055del p.V1681_ C1685del c.5169C>G p.Y1723* Splicing affecting variants c.3191-2A>G Predicted change at acceptor site 2 bps downstream: 100% c.3329-2A>G Predicted change at acceptor site 2 bps downstream: 100% c.4667&#fe;2T>C Predicted change at donor site 2 bps upstream: 100% generalized choriocapillaris dystrophy have the occasional hallmarks of early Stargardt disease, such as vermillion fundus, fundus hyperautofluorescence, and a dark choroid on fluorescein angiograms. Login to comment

PMID: 25082885 [PubMed] Alapati A et al: "Molecular diagnostic testing by eyeGENE: analysis of patients with hereditary retinal dystrophy phenotypes involving central vision loss."

No. Sentence Comment

39 Mutations and Unknown Variants Detected in Patients With Central Vision Loss Patient Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Molecular Diagnosis Late-onset retinal degeneration NA CTRP5 NA NA NA NA NA NA Sorsby fundus dystrophy Patient 1 TIMP3 1 c.113C>G p.Ser38Cys Het vAR/us Probably damaging 1 Positive Patient 2 TIMP3 1 c.113C>G p.Ser38Cys Het vAR/us Probably damaging 1 Positive Patient 3 TIMP3 5 c.610A>T p.Ser204Cys Het Mut Positive Doyne honeycomb dystrophy Patient 1 EFEMP1 9 c.1033C>T p.Arg345Trp Het Mut Positive Patient 2 EFEMP1 9 c.1033C>T p.Arg345Trp Het Mut Positive Patient 3 EFEMP1 IVS10 c.IVS10-14C>T None Het vAR/us NA NA Unconfirmed Best macular dystrophy Patient 1 BEST1 2 c.28G>A p.Ala10Thr Het Mut Positive Patient 2 BEST1 2 c.47C>T p.Ser16Phe Het Mut Positive Patient 3 BEST1 2 c.72G>T p.Trp24Cys Het Mut Positive Patient 4 BEST1 3 c.240C>A p.Phe80Leu Het Mut Positive Patient 5 BEST1 3 c.240C>A p.Phe80Leu Het Mut Positive Patient 6 BEST1 4 c.248G>C p.Gly83Ala Het vAR/us Probably damaging 1 Positive Patient 7 BEST1 4 c.277T>C p.Trp93Arg Het vAR/us Probably damaging 1 Positive Patient 8 BEST1 4 c.279G>C p.Trp93Cys Het Mut Positive Patient 9 BEST1 6 c.652C>T p.Arg218Cys Het Mut Positive Patient 10 BEST1 6 c.652C>T p.Arg218Cys Het Mut Positive Patient 11 BEST1 6 c.680A>G p.Tyr227Cys Het Mut Positive Patient 12 BEST1 6 c.741G>A p.Arg218His Het Mut Positive Patient 13 BEST1 6 c.741G>A p.Arg218His Het Mut Positive Patient 14 BEST1 7 c.727G>A p.Ala243Thr Het Mut Positive Patient 15 BEST1 7 c.727G>A p.Ala243Thr Het Mut Positive Patient 16 BEST1 7 c.728C>T p.Ala243Val Het Mut Positive Patient 17 BEST1 7 c.728C>T p.Ala243Val Het Mut Positive Patient 18 BEST1 8 c.880C>T p.Leu294Phe Het vAR/us Probably damaging 1 Positive Patient 19 BEST1 8 c.887A>G p.Asn296Ser Het Mut Positive Patient 20 BEST1 8 c.903T>G p.Asp301Glu Het Mut Positive Patient 21 BEST1 8 c.903T>G p.Asp301Glu Het Mut Positive Patient 22 BEST1 8 c.910G>A p.Asp304Asn Het Mut Positive Patient 23 BEST1 8 c.925T>C p.Trp309Arg Het vAR/us Probably damaging 1 Positive Patient 24 BEST1 8 c.929T>C p.Ile310Thr Het Mut Positive Patient 25, case 3 BEST1 4 c.250T>G p.Phe84Val Het vAR/us Probably damaging 1 Positive Pattern dystrophy Patient 1 ABCA4 6 c.634C>T p.Arg212Cys Het Mut Positive ABCA4 30 c.4469G>A p.Cys1490Tyr Het Mut Patient 2 ABCA4 17 c.2588G>C p.Gly863Ala Het Mut Unconfirmed Patient 3 ABCA4 IVS26 c.3862&#fe;3A>G Abnormal splicing Het vAR/us Unconfirmed Patient 4 PRPH2 1 c.271T>A p.Tyr91Asn Het vAR/us Probably damaging 0.909 Positive PRPH2 1 c.310-313del(AT) p.Ile104Val Het Mut Patient 5, case 6 PRPH2 1 c.422A>G p.Tyr141Cys Het Mut Positive Patient 6 PRPH2 1 c.422A>G p.Tyr141Cys Het Mut Positive Patient 7 PRPH2 1 c.515G>A p.Arg172Gln Het Mut Positive Patient 8 PRPH2 2 c.583C>T p.Arg195Stop Het Mut Positive Patient 9 PRPH2 2 c.629C>G p.Pro210Arg Het Mut Positive Patient 10 PRPH2 2 c.635G>C p.Ser212Thr Het Mut Positive Patient 11 PRPH2 2 c.683C>T p.Thr228Ile Het Mut Positive Patient 12 PRPH2 2 c.708C>G p.Tyr236Stop Het Mut Positive Patient 13, case 4 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive TABLE 2. Continued Patient Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Molecular Diagnosis Patient 14 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive Patient 15 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive Patient 16 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut Positive Patient 17, case 2 ABCA4 IVS38 c.5461-10T>C None Het Mut Unconfirmed Patient 18 PRPH2 2 c.584G>A p.Arg195Gln Het vAR/us Probably damaging 1 Positive Cone-rod dystrophy Patient 1, dominant GUCY2D 13 c.2512C>T p.Arg838Cys Het Mut Positive Patient 2, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive Patient 3, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive Patient 4, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive Patient 5, dominant GUCY2D 13 c.2513G>A p.Arg838His Het Mut Positive CRX 3 c.607T>C p.Ser213Pro Het vAR/us Probably damaging 0.999 Patient 6, recessive ABCA4 2 c.156T>G p.His52Gln Het vAR/us Probably damaging 0.998 Positive ABCA4 3 c.161G>A p.Cys54Tyr Het Mut ABCA4 28 c.4169T>C p.Leu1390Pro Het Mut Patient 7, recessive ABCA4 16 c.2385C>T p.Ser795Arg Het vAR/us Probably damaging 0.99 Positive ABCA4 IVS40 c.5714&#fe;5G>A Splice Het Mut Patient 8, recessive ABCA4 42 c.5882G>A p.Gly1961Glu Het Mut Positive ABCA4 45 c.6221G>T p.Gly2074Val Het vAR/us Probably damaging 1 Patient 9, recessive ABCA4 IVS42 c.5898&#fe;1G<A Splice Het Mut Positive ABCA4 IVS42 c.5899-2delA Splice Het Mut Patient 10, recessive ABCA4 5 c.559C>T p.Arg187Cys Het Mut Positive ABCA4 40 c.5645T>C p.Met1882Thr Het Mut Patient 11, recessive ABCA4 6 c.768G>T p.Val256Val (abnlspl) Het Mut Positive ABCA4 31 c.4577C>T p.Thr1526Met Het Mut Patient 12, recessive ABCA4 12 c.1622T>C p.Leu541Pro Het Mut Positive ABCA4 21 c.3113C>T p.Ala1038Val Het Mut ABCA4 12 c.1622T>C p.Leu541Pro Hom Mut ABCA4 21 c.3113C>T p.Ala1038Val Hom Mut ABCA4 22 c.3322C>T p.Arg1108Cys Het Mut Patient 13, recessive ABCA4 12 c.1622T>C p.Leu541Pro Hom Mut Positive ABCA4 21 c.3113C>T p.Ala1038Val Hom Mut Patient 14, recessive ABCA4 13 c.1927G>A p.Val643Met Het Mut Positive ABCA4 24 c.3602T>G p.Leu1201Arg Het Mut ABCA4 36 c.5186T>C p.Leu1729Pro Het Mut Patient 15, recessive ABCA4 23 c.3364G>A p.Glu1122Lys Het Mut Positive ABCA4 48 c.6529G>A p.Asp2177Asn Het Mut Patient 16, recessive ABCA4 35 c.4918C>T p.Arg1640Trp Het Mut Positive ABCA4 28 c.4222T>C p.Trp1408Arg Het Mut Patient 17, recessive ABCA4 11 c.1532G>A p.Arg511His Het Mut Unconfirmed Patient 18, recessive ABCA4 27 c.3899G>A p.Arg1300Gln Het vAR/us Benign 0.143 Unconfirmed Patient 19, recessive ABCA4 13 c.1933G>A p.Asp645Asn Het Mut Unconfirmed Patient 20, recessive ABCA4 35 c.4918C>T p.Arg1640Trp Het Mut Unconfirmed Patient 21, recessive ABCA4 IVS7 c.859-9T>C Unknown Hom vAR/us NA NA Unconfirmed Molecular Diagnostic Testing by eyeGENE IOVS j September 2014 j Vol. 55 j No. 9 j were screened for the p.Arg838His mutation in GUCY2D, and mutations in the CRX, ELOVL4, PRPH2, and/or ABCA4 genes. 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116 Mutations or Unknown Variants Detected in Patients With Central Vision Loss Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Frequency* Variant ID Late-onset retinal degeneration CTRP5 NA NA NA NA NA NA NA NA NA Sorsby fundus dystrophy TIMP3 1 c.113C>G p.Ser38Cys Het vAR/us Probably damaging 1 2 TIMP3 5 c.610A>T p.Ser204Cys Het Mut 1 CM941325/ rs137853298 Doyne honeycomb dystrophy EFEMP1 9 c.1033C>T p.Arg345Trp Het Mut 2 CM990504 EFEMP1 IVS10 c.IVS10-14C>T None Het vAR/us NA NA 1 Best macular dystrophy BEST1 2 c.28G>A p.Ala10Thr Het Mut 1 CM982017 BEST1 2 c.47C>T p.Ser16Phe Het Mut 1 CM010520 BEST1 2 c.72G>T p.Trp24Cys Het Mut 1 CM982018 BEST1 3 c.240C>A p.Phe80Leu Het Mut 2 CM004423 BEST1 4 c.248G>C p.Gly83Ala Het vAR/us Probably damaging 1 1 BEST1 4 c.277T>C p.Trp93Arg Het vAR/us Probably damaging 1 1 BEST1 4 c.279G>C p.Trp93Cys Het Mut 1 rs28940273/ CM982021 BEST1 6 c.652C>T p.Arg218Cys Het Mut 2 CM982023 BEST1 6 c.680A>G p.Tyr227Cys Het Mut 1 CM982024 BEST1 6 c.741G>A p.Arg218His Het Mut 2 CM003486 BEST1 7 c.727G>A p.Ala243Thr Het Mut 2 CM004434 BEST1 7 c.728C>T p.Ala243Val Het Mut 2 rs28940570/ CM00841 BEST1 8 c.880C>T p.Leu294Phe Het vAR/us Probably damaging 1 1 BEST1 8 c.887A>G p.Asn296Ser Het Mut 1 CM010524 BEST1 8 c.903T>G p.Asp301Glu Het Mut 2 CM991243 BEST1 8 c.910G>A p.Asp304Asn Het Mut 1 CM024219 BEST1 8 c.925T>C p.Trp309Arg Het vAR/us Probably damaging 1 1 BEST1 8 c.929T>C p.Ile310Thr Het Mut 1 CM000843 BEST1 4 c.250T>G p.Phe84Val Het vAR/us Probably damaging 1 1 Pattern dystrophy ABCA4 6 c.634C>T p.Arg212Cys Het Mut 1 rs61750200 ABCA4 17 c.2588G>C p.Gly863Ala Het Mut 1 CM970003/ rs76157638 ABCA4 IVS26 c.3862&#fe;3A>G Abnormal splicing Het vAR/us 1 NA ABCA4 30 c.4469G>A p.Cys1490Tyr Het Mut 1 CM990056/ rs61751402 ABCA4 IVS38 c.5461-10T>C None Het Mut 1 CS057513 PRPH2 1 c.271T>A p.Tyr91Asn Het vAR/us Probably damaging .909 1 PRPH2 1 c.310-313del(AT) p.Ile104Val Het Mut 1 NA/Deletion PRPH2 1 c.422A>G p.Tyr141Cys Het Mut 2 CM010125/ rs61755781 PRPH2 1 c.515G>A p.Arg172Gln Het Mut 1 CM930637/ rs61755792 PRPH2 2 c.583C>T p.Arg195Stop Het Mut 1 CM032999 PRPH2 2 c.629C>G p.Pro210Arg Het Mut 1 CM941210 PRPH2 2 c.635G>C p.Ser212Thr Het Mut 1 CM971289/ rs61755801 PRPH2 2 c.683C>T p.Thr228Ile Het Mut 1 TMP_ESP_6_ 42672248 PRPH2 2 c.708C>G p.Tyr236Stop Het Mut 1 rs61755813 PRPH2 IVS2 c.828&#fe;3A>T Splice Het Mut 4 CS010139 PRPH2 2 c.584G>A p.Arg195Gln Het vAR/us Probably damaging 1 1 TABLE 3. Continued Gene Exon DNA Change Protein Change Genotype Result PolyPhen Description PolyPhen Score Frequency* Variant ID Cone-rod dystrophy ABCA4 2 c.156T>G p.His52Gln Het vAR/us Probably damaging 0.998 1 ABCA4 3 c.161G>A p.Cys54Tyr Het Mut 1 CM990012/ rs150774447 ABCA4 28 c.4169T>C p.Leu1390Pro Het Mut 1 CM014810/ rs61752430 ABCA4 16 c.2385C>T p.Ser795Arg Het vAR/us Probably damaging 0.99 1 ABCA4 IVS40 c.5714&#fe;5G>A Splice Het Mut 1 CS982057 ABCA4 27 c.3899G>A p.Arg1300Gln Het vAR/us Benign 0.143 1 ABCA4 32 c.4661A>G p.Glu1554Gly Het vAR/us Benign 0.326 1 ABCA4 30 c.4383G>A p.Trp1461Stop Het Mut 1 Stop/NA ABCA4 IVS38 c.5461-10T>C None Het Mut NA NA 2 CS057513 ABCA4 22 c.3259G>A p.Glu1087Lys Het Mut 1 CM970008/ rs61751398 ABCA4 42 c.5882G>A p.Gly1961Glu Het Mut 2 CM970016/ rs1800553 ABCA4 45 c.6221G>T p.Gly2074Val Het vAR/us Probably damaging 1 1 ABCA4 IVS42 c.5898&#fe;1G<A Splice Het Mut 1 CS011524 ABCA4 IVS42 c.5899-2delA Splice Het Mut 1 rs3112831 CRX 3 c.607T>C p.Ser213Pro Het vAR/us Probably damaging 0.999 1 ABCA4 5 c.559C>T p.Arg187Cys Het Mut 1 COSM913472 ABCA4 40 c.5645T>C p.Met1882Thr Het Mut 1 rs4147830 ABCA4 6 c.768G>T p.Val256Val (abnlspl) Het Mut 1 CM990057/ rs61750152 ABCA4 31 c.4577C>T p.Thr1526Met Het Mut 1 rs62645944 ABCA4 11 c.1532G>A p.Arg511His Het Mut 1 rs140482171 ABCA4 12 c.1622T>C p.Leu541Pro Het Mut 1 CM990022/ rs61751392 ABCA4 21 c.3113C>T p.Ala1038Val Het Mut 1 CM970006/ rs61751374 ABCA4 12 c.1622T>C p.Leu541Pro Hom Mut 2 CM990022/ rs61751392 ABCA4 21 c.3113C>T p.Ala1038Val Hom Mut 2 CM970006/ rs61751374 ABCA4 22 c.3322C>T p.Arg1108Cys Het Mut 1 CM990039/ rs61750120 ABCA4 13 c.1927G>A p.Val643Met Het Mut 1 CM014293/ rs61749417/ rs143548435 ABCA4 24 c.3602T>G p.Leu1201Arg Het Mut 1 CM990042/ rs61750126 ABCA4 36 c.5186T>C p.Leu1729Pro Het Mut 1 CM990062/ rs61750567 ABCA4 13 c.1933G>A p.Asp645Asn Het Mut 1 rs617494181933 ABCA4 23 c.3364G>A p.Glu1122Lys Het Mut 1 CM990041 ABCA4 48 c.6529G>A p.Asp2177Asn Het Mut 1 CM970023/ rs1800555 ABCA4 35 c.4918C>T p.Arg1640Trp Het Mut 2 CM983728/ rs61751404 ABCA4 28 c.4222T>C p.Trp1408Arg Het Mut 1 CM990048/ rs61750135 GUCY2D 13 c.2512C>T p.Arg838Cys Het Mut 1 rs61750172 GUCY2D 13 c.2513G>A p.Arg838His Het Mut 5 CM012606/ rs61750173 ABCA4 IVS7 c.859-9T>C Unknown Hom vAR/us NA NA 1 ABCA4 42 c.5882G>A p.Gly1961Glu Hom Mut 1 CM970016/ rs1800553 ABCA4 43 c.5917delG Deletion Hom Mut 1 RISN_ABCR: c.5917delG Molecular Diagnostic Testing by eyeGENE IOVS j September 2014 j Vol. 55 j No. 9 j Six patients with late-onset retinal pathology and drusen had well-characterized clinical data. 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PMID: 25139735 [PubMed] Lee W et al: "The external limiting membrane in early-onset Stargardt disease."

No. Sentence Comment

86 [L541P;A1038V] ND P3 7 Caucasian 20/40 (0.30) 20/30 (0.18) 1 1 ND p. Login to comment
87 [L541P;A1038V] ND P4 13 Caucasian 20/80 (0.60) 20/50 (0.40) 2 1 Mid ND p.P1380L c.5714&#fe;5G>A P5 14 Caucasian 20/200 (1.00) 20/150 (0.88) 1 1 Late 0.5 p.P1380L c.5714&#fe;5G>A P6 13 Caucasian 20/40 (0.30) 20/50 (0.40) 2 1 Late ND p. Login to comment
88 [L541P;A1038V] p.L2027F P7 8 Caucasian n/a n/a 1 n/a ND p. Login to comment
89 [L541P;A1038V] p.L2027F P8 10 Caucasian 20/40 (0.30) 20/80 (0.60) 1 1 None-early 1 p.R1108C p.Q1412* P9 14 Caucasian 20/100 (0.70) 20/100 (0.70) 2 1 Early-late 0.5 p.T972N p.L2027F P10 9 Caucasian 20/150 (0.88) 20/400 (1.30) 2 1 Late ND c.5312&#fe;1G>A p.R2030* P11 15 Caucasian 20/200 (1.00) 20/200 (1.00) 2 2 Mid-late 3 p.L2027F p.R2077W P12 5 Caucasian 20/30 (0.18) 20/40 (0.30) 1 n/a ND c.5018&#fe;2T>C p.G1961E P13 10 Caucasian 20/200 (1.00) 20/200 (1.00) 2 2 Mid 4 p. Login to comment
90 [L541P;A1038V] p.R1640W P14 12 Caucasian 20/200 (1.00) 20/200 (1.00) 2 2 Late 6 p. Login to comment
91 [L541P;A1038V] p.R1640W P15 16 Caucasian 20/200 (1.00) 20/200 (1.00) 2 n/a Mid-late 8 p.K346T p.T1117I P16 9 Caucasian 20/150 (0.88) 20/150 (0.88) 1 n/a 1 p.P1380L p.G1961E P17 18 Caucasian 20/40 (0.30) 20/150 (0.88) 1 1 Early 3 p.P1380L p.G1961E P18ߥ 18 Caucasian 20/150 (0.88) 20/150 (0.88) 2 1 Late 4 p. Login to comment
92 [L541P;A1038V] p.L2027F P19 16 Caucasian 20/150 (0.88) 20/150 (0.88) 1 n/a Early 6 p.G863A p. Login to comment

PMID: 25283059 [PubMed] Duncker T et al: "Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy."

No. Sentence Comment

65 Sex Age (yrs) Race or Ethnicity Best-Corrected Visual Acuity (Logarithm of the Minimum Angle of Resolution Units) Genetic Data Average of Quantitative Fundus Autofluorescence Values of the 8 Segments ABCA4 Mutations Right Eye Left Eye Allele 1 Allele 2 Right Eye Left Eye 1 M 36 White 0.70 0.70 p.G1961E p.G1961E 282 279 2 F 46 White 0.40 0.40y p.G1961E p.R1129C 391 3 M 17 Asian Indian 0.70 0.88 p.G1961E c.6729&#fe;4_&#fe;18del 340 363 4 M 17 White 0.88 0.88 p.G1961E p.A1773V 340 366 5 M 21 White 0.88 0.88 p.G1961E p.W15* 341 325 6 F 22 White 0.70 0.48 p.G1961E p.G863A 361 351 7 F 20 White 0.70z 0.88z p.G1961E p.L541P 317 8 M 12 White 0.80 0.70 p.G1961E p.P1380L 251 242 9 F 21 White 0.88 0.88 p.G1961E p.R212C 407 439 10 F 26 White 0.40z 0.70z p.G1961E c.5196&#fe;1056A/G 379 344 11 F 24 White 0.88z 0.88z p.G1961E p.C2150R 405 396 12 F 24 White 0.30z 0.18z p.G1961E p.N96D 513 549 13 F 20 White 0.30 0.40 p.G1961E p.N96D 397 355 14 M 25 White 0.00y 0.30 p.G1961E p.Q1003* 322 328 15 M 8.2 White 0.88 0.88 p. Login to comment
66 [L541P; A1038V] 438 432 16 M 25 White 0.60 0.60 p.S84fs p.R2107H 294 17 F 24 Black 0.70 0.88 p.G991R p.L1138P 321 326 18 M 26 White 0.00y 0.00y p.R1300* p.R2106C 419 412 19 M 11 White 0.40z 0.40z p.W821R p.C2150Y 304 296 20 F 16 White 0.70 0.40 p.K1547* p.R2030Q 481 513 21 F 13 White 1.30 1.00 pR1108C p.Q1412* 511 528 22 F 18 White 0.00 0.00 p.G863A c.5898&#fe;1G/A 465 431 Mutations in Other Genes 23 F 16 White 0.40 0.48 GUCY2D e p.R838H 152 165 24 M 53 Black 0.88 0.88 CNGA3 e p. Login to comment
170 This is illustrated in Figure 8, in which disease progression over 2.5 years is shown for the brother of patient 15, who also carries the complex allele L541P/ A1038V. Login to comment
187 This ABCA4-positive patient was not included in the study (because of presence of peripheral flecks), but he also carries the complex allele L541P/A1038V. Login to comment

PMID: 25301883 [PubMed] Noupuu K et al: "Structural and genetic assessment of the ABCA4-associated optical gap phenotype."

No. Sentence Comment

83 [1622T > C;3113C > T];[5882G > A] p.[(L541P;A1038V)];[(G1961E)] P6, F*ߤ c. Login to comment
84 [1622T > C;3113C > T];[5882G > A] p.[(L541P;A1038V)];[(G1961E)] P7, F*ߤ c. Login to comment
85 [1622T > C];[5882G > A] p.[(L541P)];[(G1961E)] P8, F*ߤ c. Login to comment
86 [1622T > C];[5882G > A] p.[(L541P)];[(G1961E)] P9, Fߤ c. Login to comment
94 [1622T > C;4328G > A];[5882G > A] p.[(L541P;R1443H)];[(G1961E)] * Sibling pairs: P1 and P2, P3 and P4, P5 and P6, P7 and P8. Login to comment
186 Of the other disease-associated ABCA4 alleles compound heterozygous with p.G1961E, the p.L541P mutation, presenting alone or as a complex allele with the p.A1038V variant, was observed in seven cases (four unrelated) with optical gap (Table 2 and Supplementary Table S1) while only once in patients without the phenotype (Supplementary Table S1). Login to comment
189 Therefore, we can conclude that the p.G1961E variant, maybe sometimes together with the p.L541P or p. (L541P; A1038V) allele, is currently the only ABCA4 mutation associated with the optical gap phenotype. Login to comment

PMID: 25342616 [PubMed] Duncker T et al: "Correlations among near-infrared and short-wavelength autofluorescence and spectral-domain optical coherence tomography in recessive Stargardt disease."

No. Sentence Comment

87 [L541P;A1038V] 4 3 8.2 M White Hazel (0.9) 0.9 p. Login to comment
88 [L541P;A1038V] 4 4 17.9 M Indian Brown 0.7 0.9 p.G1961E c.6729&#fe;4_&#fe;18del 3 5 12.1 M White Green 0.8 0.7 p.G1961E p.P1380L 3 6 46.4 M Black Brown 0.3 0.8 p.T1526M 2 7 42.6 F White Brown 1.3 1.3 p.G1961E p. Login to comment
89 [L541P;A1038V] 2 8 42.8 M White Blue 0.9 0.4 c.571-1G>T 1 9 24.6 F White Hazel 0.3 0.2 p.G1961E p.N96D 5 10 21.9 F White Brown 0.3 0.4 p.G1961E p.N96D 5 11 25.3 M White Brown 0.0 0.3 p.G1961E p.Q1003* 3 12 8.5 M White Green n/a (n/a) p. Login to comment
90 [L541P;A1038V] p.L2027F 4 13 19.7 M White Brown 0.9 0.9 p.G1961E p. Login to comment
91 [L541P;A1038V] 5 14 22.4 F White Brown 0.8 0.8 p.R212C 3 15 20.2 M White Brown 0.9 0.9 p.G1961E p.P1380L 1 16 27.6 M Arabic Brown 0.0 0.0 p.R1300* p.R2106C 3 17 26.8 M White Blue 0.5 0.5 p.G1961E c.3050&#fe;5G>A 1 18 24.9 F White Hazel 0.9 0.9 p.G1961E p.C2150R 5 19 13.2 M White Blue 0.9 1.0 p.W821R p.C2150Y 3 20 61.0 F White Green 2.0 0.0 c.250_251insCAAA 2 21 36.3 F White Blue 1.3 0.1 p.N1799D 1 22 14.1 F White Green 1.0 0.9 p.R1108C p.Q1412* 2 23 18.6 M White Brown 0.9 0.9 p.G1961E p.A1773V 3 24 53.3 F White Blue 0.3 (0.2) p.R2077W 2 BCVA values in parenthesis indicate fellow eyes that were not included in the study. Login to comment
167 Interestingly, these patients were the youngest in our cohort and all carried the complex allele L541P/A1038V. Login to comment
168 The latter mutations are located in the exocytoplasmic domain-1 and nucleotide binding domain-1 and confer severe and relatively early-onset retina-wide disease.37-40 In recent work using quantitative fundus AF, we also reported that the L541P/ A1038V complex allele confers particularly high levels of fundus AF.4 At positions where EZ is disrupted, the NIR-AF signal may be detectable even if the RPE cells are dysfunctional. Alternatively, this pattern could indicate that in these cases photoreceptor cells die first. Login to comment

PMID: 25444351 [PubMed] Lambertus S et al: "Early-onset stargardt disease: phenotypic and genotypic characteristics."

No. Sentence Comment

137 11 13 16, 23, 32, 39 c.818G>A p.Trp273* 1 1 This study c.872C>T p.Pro291Leu 1 1 34 c.1622T>C p.Leu541Pro 2 2 1, 16, 32, 40 c.1822T>A p.Phe608Ile 4 5 1, 23 c.1957C>T p.Arg653Cys 1 1 32, 41 c.2588G>C p.Gly863Ala/p.DelGly863 3 4 16, 18, 23, 32, 42 c.2919-?_3328&#fe;?del p.Ser974_Gly1110delinsCys 2 2 23 c.2947A>G p.Thr983Ala 3 4 34 c.3113C>T p.Ala1038Val 2 2 16, 31, 32, 40, 43 c.3335C>A p.Thr1112Asn 1 1 23 c.3449G>A p.Cys1150Tyr 1 1 This study c.3813G>C p.Glu1271Asp 1 1 This study c.3874C>T p.Gln1292* 1 1 34 c.4224G>T p.Trp1408Cys 1 1 This study c.4462T>C p.Cys1488Arg 1 1 1, 8, 44, 45 c.4506C>A p.Cys1502* 1 1 34 c.4539&#fe;1G>T p.? Login to comment

PMID: 25884411 [PubMed] Grassmann F et al: "Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy)."

No. Sentence Comment

95 Table 2 Genetic variants identified in ABCA4 sequence analysis in CQ-treated patients with (cases) and without (controls) toxic maculopathy Frequency in Variant (NM_000350.2) Amino acid exchange (NP_000341.2) Cases Controls EURߤ Raw p-value FDR# c.324G > A M114I 0.00 0.04 - - - c.635G > A R212H 0.06 0.08 0.06 - - c.1268A > G* H423R 0.29 0.23 0.30 0.58783 0.58783 c.1269C > T H423H 0.13 0.04 0.07 - - c.1622T > C L541P 0.02 0.00 - - - c.2588G > C G863A 0.00 0.04 0.00 - - c.2828G > A R943Q 0.04 0.12 0.04 - - c.3113C > T A1038V 0.02 0.00 0.00 - - c.4203C > A P1401P 0.00 0.04 - - - c.4297G > A V1433I 0.00 0.04 0.00 - - c.5603A > T N1868I 0.06 0.08 0.07 - - c.5682G > C* L1894L 0.13 0.38 0.26 0.02292 0.030 c.5814A > G* L1938L 0.06 0.31 0.18 0.00722 0.014 c.5843C > T P1948L 0.04 0.08 0.04 - - c.5844A > G* P1948P 0.06 0.31 0.19 0.00722 0.014 c.6069T > C I2023I 0.04 0.08 0.06 - c.6148G > C V2050L 0.02 0.00 0.00 - - c.6249C > T I2083I 0.04 0.08 0.05 - - c.6282 + 7G > A - 0.04 0.08 0.05 - - c.6285T > C D2095D 0.08 0.15 0.10 - - c.6357A > G E2119E 0.02 0.00 - - - c.6730-3T > C - 0.02 0.12 0.02 - - c.6764G > T S2255I 0.02 0.12 0.02 - - *Common variants (combined frequency in cases and controls > 11.6%). Login to comment

PMID: 26024099 [PubMed] Duncker T et al: "Quantitative Fundus Autofluorescence and Optical Coherence Tomography in PRPH2/RDS- and ABCA4-Associated Disease Exhibiting Phenotypic Overlap."

No. Sentence Comment

61 [L541P;A1038V] NS 425 n/a 3ߤ M 34.5 White 0.18 0.18 p.G1961E p. Login to comment
62 [L541P;A1038V] NS 356 352 4 F 35.8 White 0.00 0.00 NF NF p.C213S 513 444 5 F 43.4 White 0.00 0.00 NF NF NF 489 424 6 M 34.2 White n/a n/a NF NF NF 293 302 7 M 58.9 White 1.00 0.88 NF NF NF 288 n/a 8 F 62.4 White 0.30 0.30 NF NF c.582-1G>A 479 535 9 F 60.3 White 0.88 0.88 c.4248_4250delCTT NF NF 510 457 10 M 57.9 White 0.60 0.60 NF NF NF n/a 384 11ߥ F 56.8 White 0.18 0.18 NF NF c.163delT 398 370 12* F 53.9 White 0.00 0.00 NF NF p.Y91N;c.310_313delATCT 536 564 13* F 47.9 White 0.00 0.30 NF NF p.Y91N;c.310_313delATCT 510 524 14 F 42.2 White 0.48 0.48 c.2069delG NF NF 541 571 15 F 52.8 White 0.00 0.00 NF NF NF 355 n/a 16 M 42.8 White 0.88 0.40 c.571-1G>T NF NF 518 529 17 M 42.8 White 0.10 0.00 NF NF NF 164 162 18 F 38.5 White 0.12 0.00 c.250_251insCAAA NF NF n/a 624 19 M 50.2 Asian&#a7; 0.60 0.70 p.V675I p.M1882I NF 471 502 20ߥ F 36.1 White 0.30 0.30 NF NF c.163delT 736 751 21 F 50.8 White 0.48 0.40 NF NF NF 396 367 22 M 48.6 Black 1.00 0.48 NF NF NF 351 339 23 F 25.6 White 1.00 1.00 p.G1961E p. Login to comment
63 [L541P;A1038V] NS n/a 443 24 F 20.2 White 0.88 0.88 p.G1961E p.P1380L NS 376 400 25 F 22.9 White 0.88 0.80 p. Login to comment
65 [L541P;R1443H] NS 479 487 32 F 23 White 0.30 0.18 p.G1961E p.P1380L NF 412 444 33 M 28.4 White 0.70 0.48 NF NF NF 388 n/a 34ߥ M 61.5 White 1.30 0.60 NF NF E191Xjj 490 459 35ߥ M 30.6 White 0.00 0.00 NF NF E191Xjj 345 324 36 M 51.5 White 0.30 0.54 NF NF NF 515 497 37 M 53.2 White 0.60 0.60 NF NF NF 212 239 38 F 35.3 White 0.88 0.10 p.N1799D NF NF n/a 387 39 F 55 White 0.00 0.00 p.R2077W NF NF 541 586 BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; OD, right eye; OS, left eye; qAF8, average quantitative autofluorescence of the 8 measurement sites from all available images per eye; n/a, not available; NF, not found. Login to comment

PMID: 26024107 [PubMed] Greenstein VC et al: "Near-infrared autofluorescence: its relationship to short-wavelength autofluorescence and optical coherence tomography in recessive stargardt disease."

No. Sentence Comment

74 Selected Demographic, Clinical, and Genetic Characteristics of the Study Cohort Patient Sex Disease-Associated ABCA4 Variant(s) Age Eye BCVA 1 F p.G1961E; c2382&#fe;1G>A 36 OS 0.8 2 M p.[L541P;A1038V] 8 OS 0.6 3 M p.G1961E; c.6729&#fe;5_&#fe;19del 18 OS 0.9 4 M p.P1380L; p.G1961E 12 OD 0.8 5 M c.571-1G>T 43 OD 0.4 6 M p.Q1003*; p.G1961E 25 OS 0 7 M p.[L541P;A1038V]; p.L2027F 8 OD N/A 8 F p.R212C; p.G1961E 22 OD 0.8 9 F p.P1380L; p.G1961E 20 OD 0.9 10 M p.R1300*; p.R2106C 26 OS 0 11 M c.3050&#fe;5G>A; p.G1961E 27 OD 0.5 12 F p.G1961E; p.C2150R 25 OD 0.7 13 M p.W821R; p.C2150Y 13 OD 0.4 14 F p.N1799D 36 OD 1.3 15 M p.A1773V; p.G1961E 19 OD 0.7 FIGURE 1. Login to comment

PMID: 26207301 [PubMed] Park JC et al: "Objective Analysis of Hyperreflective Outer Retinal Bands Imaged by Optical Coherence Tomography in Patients With Stargardt Disease."

No. Sentence Comment

52 of ABCA4 Mutations Mutation(s) 1 13 M 20/70 2 p.[(L541P; A1038V)] (;)c.5714&#fe;5G>A 2 15 F 20/60 2 c.3050&#fe;5G>A(;)p.(G1961E) 3 15 F 20/80 2 p.[(R1129L(;)A1773V)] 4 16 F 10/1001 Sister of patient 3 5 20 M 20/160&#fe;2 2 p.[(R1129C(;)R2077W)] 6 20 F 20/1601 2 p.[(G1961E(;)R2040*)] 7 21 M 20/40 2 p.[(R219T(;)W439*(;)G863A)] 8 23 F 10/100 2 c.5461-10T>C(;)p.(G1961E) 9 23 F 20/1001 2 c.302&#fe;1G>A(;)p.(R2107H) 10 28 F 20/1001 2 c.5461-10T>C(;)p.(G1961E) 11 30 F 20/25&#fe;2 1 p.[(R2077W)];[?] Login to comment
54 14 33 F 20/200 2 p.[(L541P;A1038V(;)I1684N)] 15 41 F 20/25&#fe;1 2 p.[(V989A)];[(V989A)] 16 45 F 20/25 2 p.[(I975M(;)K1978E)] 17 45 M 20/200 2 p.[(R1108C;Q876P)];[(Q876P)] 18 47 F 20/200 2 p.[(R1108C(;)G1961E)] 19 48 M 20/253 2 p.[(G1961E)];[(G1961E)] 20 48 M 20/100 2 p.[(G863A)];[(G863A)] BCVA, best-corrected visual acuity; ''?`` indicates that the second mutation was not identified. Login to comment

PMID: 26230768 [PubMed] Sparrow JR et al: "Flecks in Recessive Stargardt Disease: Short-Wavelength Autofluorescence, Near-Infrared Autofluorescence, and Optical Coherence Tomography."

No. Sentence Comment

48 [IVS15&#fe;1G>A 2 M 12.00 Caucasian 0.5 0.5 p. [L541P; A1038V] 3* M 9.00 Caucasian 1 1 p. [W855*]; [T1526M] 4 F 47.55 Caucasian 1.3 1.3 p. [L541P; A1038V]; [G1961E] 5* F 16.47 Caucasian 0.6 0.6 p. [T972N]; [L2027F] 6* M 16.98 Caucasian 1.3 1.3 p. [K346T]; [T1117I] 7 F 23.80 Caucasian 0.6 0.4 p. [R1161S] 8* F 28.67 Caucasian 1.3 1.3 p. [P1380L]; [P1380L] 9 M 42.83 Caucasian 0.9 0.4 c. Login to comment
49 [571-1G>T 10* M 13.89 Caucasian 0.4 0.4 p. [L541P; A1038V]; [L2027F] 11* F 20.20 Caucasian 0.9 0.9 p. [P1380L]; [G1961E] 12 M 27.61 African-Arab 0 0 p. [R1300*]; [R2106C] 13* M 46.93 Caucasian 0.3 0.4 p. [C1490Y]; [G1961E] 14* M 26.82 Caucasian 0 0 c. Login to comment

PMID: 26377081 [PubMed] Cideciyan AV et al: "Predicting Progression of ABCA4-Associated Retinal Degenerations Based on Longitudinal Measurements of the Leading Disease Front."

No. Sentence Comment

153 example, among the 14 patients compound heterozygous for the common G1961E allele (Supplementary Table S1), the model would predict foveal disease in the first decade of life for three alleles (P68L;G1961E, L541P;A1038V, and T1019M), second decade of life for four alleles (R1129L, C54Y, R152Stop, and V256V) and fourth decade of life for four alleles (P1380L, R1640Q, c.5312&#fe;1 G>A, and M669fs). Login to comment
181 Pigmented Abca4 knockout and L541P;A1038V knockin mice show substantial accumulation of lipofuscin in the RPE but show little, if any, retinal degeneration.61,75 Albino Abca4 knockout mice show both lipofuscin accumulation and a slow photoreceptor degeneration but similarity of photoreceptor loss in homozygote and heterozygote animals do not match the normal retinas of human heterozygote carriers.76-78 Abca4-Rdh8 double-knockout mice show hypersensitivity to acute light damage which has not been observed in human patients.59 Thus, it is currently difficult to extrapolate from preclinical experimental therapies what component and which stages of human disease may successfully be treated with different approaches. Login to comment

PMID: 26551331 [PubMed] Duncker T et al: "Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers."

No. Sentence Comment

26 [L541P;A1038V] 0.18 0.00 OD 357 339 S1.4 M 49.2 White Father c.768&#fe;358C>T 0.00 0.00 OS 322 339 S1.5 M 24.7 White Half-brother p. Login to comment
27 [L541P;A1038V] 0.00 0.00 n/a 264 n/a S1.6 M 9.7 White Brother p. Login to comment
28 [L541P;A1038V] 0.10 0.10 OS n/a 141 S2.2 F 44.4 Indian Mother c.6729&#fe;5_&#fe;19del 0.10 0.00 OS 257 291 S2.3 M 56.2 Indian Father p.G1961E 0.00 0.00 OD 475 431 S3.4 F 54.1 White Mother p.G863A 0.00 0.00 OS 459 451 S3.5 F 82.0 White Grandmother p.G863A 0.00 0.00 OD n/a n/a S4.2 F 44.6 White Mother p.W855* 0.00 0.00 OD 330 n/a S4.3 M 40.9 White Father p.T1526M 0.00 0.00 OS 283 271 S5.2 F 71.5 White Sister p.C698Y 0.00 0.10 OD n/a n/a S5.3 F 67.5 White Sister c.2160&#fe;1G>C 0.00 0.00 OS n/a n/a S5.4 F 62.9 White Sister p.C698Y 0.00 0.00 OD n/a n/a S6.2 M 54.9 Black Brother p.T1526M 0.10 0.00 OS 477 423 S7.2 F 48.9 White Mother c.5196&#fe;1G>A 0.00 0.00 OS 443 415 S8.2 F 59.6 White Mother p.K346T 0.00 0.00 OD 546 483 S8.3 M 54.6 White Father p.T1117I 0.10 0.10 OD 289 n/a S9.2 F 51.5 White Mother c.5196&#fe;1137G>A 0.00 0.00 n/a 302 n/a S9.3 M 57.8 White Father p.C54Y 0.00 0.00 OS 419 375 S10.2 M 24.1 Indian Brother p.Q2220* 0.00 0.00 OD 227 227 S11.2 F 40.0 Asian Mother c.5923del 0.00 0.18 OD 229 191 S11.3 M 40.1 Asian Father p.R408* 0.00 0.00 OD 195 178 S12.2 F 53.2 White Mother p.L2027F 0.00 0.00 n/a 355 309 S13.2 F 49.8 White Mother p.R1161S 0.00 0.00 OS 367 372 S13.3 M 22.3 White Brother p.R1161S 0.00 0.00 OD 202 206 S14.2 F 67.0 White Mother p.P1380L 0.00 0.00 OD n/a n/a S14.3 F 24.4 White Sister p.P1380L 0.00 0.00 OS n/a 163 S15.3 F 26.8 White Sister c.3050&#fe;5G>A 0.00 0.00 n/a 293 281 S16.2 M 53.7 Black Father c.4253&#fe;5G>T 0.00 0.00 n/a n/a 204 S17.2 F 60.0 Hispanic Mother p.A1038V 0.00 0.00 n/a 247 n/a S18.2 F 41.8 Indian Father c.5917del 0.00 0.00 OD n/a 194 S18.3 M 48.6 Indian Mother c.859-9T>C 0.00 0.00 OD 253 215 S18.4 F 12.9 Indian Sister c.5917del 0.00 0.00 OD 84 93 S19.4 F 58.5 White Mother p.L2027F 0.00 0.00 OD 205 n/a S19.5 M 61.6 White Father p.G851D 0.10 0.10 OD n/a n/a S20.2 F 41.5 White Mother c.5312&#fe;1G>A 0.00 0.00 n/a 335 351 S20.3 M 39.0 White Father p.R2030* 0.00 0.10 n/a 442 n/a S21.3 F 53.1 White Mother p.G1961E 0.00 0.00 OD 490 488 S22.3 M 46.3 White Father p.L2027F 0.00 0.00 OS 386 376 S22.4 F 47.1 White Mother p. Login to comment
29 [L541P;A1038V] 0.00 0.00 OS 342 326 S23.2 F 37.4 White Sister p.G1961E 0.00 0.00 OS 220 n/a S24.2 F 37.5 White Daughter c.247_250dup 0.00 0.00 OD 298 288 S25.3 F 49.9 Black Mother p.R2107H 0.88 0.10 n/a n/a 385 S26.3 F 58.2 White Mother p.G1961E 0.00 0.00 OD 238 297 S26.4 M 57.2 White Father p. Login to comment
30 [L541P;A1038V] 0.18 1.30 OS 312 279 S26.3 M 17.4 White Brother p. Login to comment
31 [L541P;A1038V] 0.10 0.00 OS 174 143 S27.2 F 46.2 White Mother p.P1380L 0.00 0.10 OD 379 320 S27.3 M 47.3 White Father p.G1961E 0.00 0.00 OD 413 384 S27.4 F 17.4 White Sister p.P1380L 0.00 0.00 OS 184 189 S28.2 F 58.9 White Mother p. Login to comment
66 [L541P;A1038V] c.768&#fe;358C>T 0.54 0.60 639 627 P 1.2&#a7; M 7.0 White p. Login to comment
67 [L541P;A1038V] c.768&#fe;358C>T 0.30 0.18 n/a 413 P 2.1ߤ M 17.9 Indian p.G1961E c.6729&#fe;5_&#fe;19del 0.70 0.88 340 363 P 3.1&#a7; F 25.1 White p.G863A c.5898&#fe;1G>A 0.80 0.80 710 675 P 3.2ߤ F 18.9 White p.G863A c.5898&#fe;1G>A 0.00 0.00 465 431 P 3.3 F 24.4 White p.G863A c.5898&#fe;1G>A 0.18 0.00 507 467 P 4.1 M 9.0 White p.W855* p.T1526M 1.00 1.00 538 n/a P 5.1 F 67.0 White p.C54Y c.2160&#fe;1G>C CF HM n/a n/a P 6.1 M 46.0 Black p.T1526M 0.30 0.80 n/a n/a P 7.1 F 25.3 White c.5196&#fe;1G>A p.S2235P 1.00 1.30 420 317 P 8.1 M 17.0 White p.K346T p.T1117I 1.30 0.70 871 828 P 9.1 M 21.5 White p.C54Y c.5196&#fe;1137G>A 0.18 0.18 609 608 P 10.1 M 31.0 Indian c. Login to comment
69 [L541P;A1038V] p.L2027F n/a n/a P 22.2 M 13.9 White p. Login to comment
70 [L541P;A1038V] p.L2027F 0.30 0.40 591 608 P 23.1ߤ F 26.0 White p.G1961E c.5196&#fe;1056A>G 0.40 0.70 379 344 P 24.1 F 52.0 White c.247_250dup 0.80 0.00 n/a n/a P 25.1 F 26.0 Black p.E526A p.R2107H 0.48 0.00 507 536 P 25.2 F 25.9 Black p.E526A p.R2107H 0.18 0.00 461 468 P 26.1&#a7; F 25.6 White p. Login to comment
71 [L541P;A1038V] p.G1961E 0.60 0.60 n/a 398 P 26.2 F 19.7 White p. Login to comment
72 [L541P;A1038V] p.G1961E 0.60 0.54 320 307 P 27.1&#a7; F 18.8 White p.P1380L p.G1961E 0.60 0.70 368 n/a P 28.1&#a7; F 22.9 White p. Login to comment
75 [W1408R;R1640W] 1.00 1.00 n/a n/a P 33.1&#a7; M 23.0 White p.R2030Q p.G1961E 1.00 1.00 334 347 P 34.1 M 46.9 White p.C1490Y p.G1961E 0.40 0.30 376 384 P 35.1ߥ M 24.8 White c.3050&#fe;5G>A p.G1961E 0.00 0.00 381 451 P 36.1ߥ F 29.3 Hispanic p.L541P p.G1961E 0.40 0.40 479 487 P 37.1ߤ F 24.7 White p.G1961E p.C2150R 0.88 0.88 405 396 P 38.1&#a7; M 11.7 White p.W821R p.C2150Y 0.40 0.40 306 n/a P 39.1 F 12.8 White p.P1380L c.5714&#fe;5G>A 0.60 0.40 558 573 P 39.2 M 14.1 White p.P1380L c.5714&#fe;5G>A 0.88 0.88 395 462 P 40.1ߤ F 16.2 White p.K1547* p.R2030Q 0.70 0.40 481 513 P 41.1 F 19.0 White p.C54Y 0.88 0.88 n/a n/a P 42.1ߤ F 13.0 White p.R1108C p.Q1412* 1.30 1.00 511 528 P 43.1ߤ M 17.4 White p.A1773V p.G1961E 0.88 0.88 340 366 P 44.1 M 14.0 Asian p.R408* c.4248_4250del 1.30 1.30 n/a n/a P 44.2 F 7.0 Asian p.R408* c.4248_4250del 1.30 1.30 n/a n/a P 45.1 F 42.4 White p.N965Y p.P1486L 0.10 0.40 n/a n/a BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; OD, right eye; OS, left eye; qAF8, average quantitative autofluorescence of the 8 measurement sites from all available images per eye; n/a, not available. Login to comment
111 [L541P; A1038V] in six carriers, p.P1380L in four carriers, and p.L2027F in three carriers. Login to comment
124 [L541P; A1038V], p.L2027F. Login to comment
137 [L541P; A1038V], p.P1380L, and p.L2027F mutations (and no p.G1961E mutation on the other allele).24 To determine whether similar differences in the segregation of qAF8 levels could also be observed for ABCA4 mutations in carriers and whether specific ABCA4 mutations may be associated with higher qAF8 levels, we plotted qAF values for carriers and affected patients who carried one of the four most common mutations (p.G1961E, p. Login to comment
138 [L541P;A1038V], p.P1380L, and p.L2027F) (Fig. 4). Login to comment
146 [L541P, A1038V] (family 26), p. Login to comment
147 [L541P; A1038V] (family 1), and p.G1961E; p.P1380L (family 27). Login to comment
163 [L541P; A1038V], p.P1380L, and p.L2027F, are indicated in color. Login to comment
170 [L541P; A1038V] conferred a faster rate of lipofuscin accumulation, whereas accumulation in the presence of the p.G1961E and p.G851D mutations was slower. Login to comment
196 Thickness profiles acquired by segmentation of spectral-domain optical coherence tomography (SD-OCT) images of carriers of ABCA4 mutations p.G1961E, p.L541P/A1038V, p.P1380L, and p.L2027F. Login to comment
206 [L541P;A1038V], have been shown to be associated with ABCA4 mislocalization; the p.L541P mutation in particular prevents correct localization of ABCA4 in OS and thus retention in inner segments.42 It is expected that under these conditions the pathogenesis of STGD1 could be exacerbated by endoplasmic reticulum (ER) stress and the unfolded-protein response (UPR).43 Since the onset of the UPR may be dependent on mutation type and gene dosage, a monoallelic p. Login to comment
207 [L541P; A1038V] mutation may leave photoreceptor cells with a limited and latent capacity to deal with other sources of ER stress. Login to comment

PMID: 26574798 [PubMed] Gaia O et al: "Cerebral Involvement in Stargardt's Disease: A VBM and TBSS Study."

No. Sentence Comment

81 Demographic and Genetic Data of STGD Patients Age Sex ABCR Mutations Age of Onset 19 F 250insCAAA G1961E D498N 4017ins24bp 11 18 M L541P/A1038V IVS40&#fe;5g->a 14 25 M L541P/A1038V G1961E 17 15 F G1961E R2149X 13 48 M N96D IVS40&#fe;5G>A 38 29 M G1961E L1938L L1894L S1689P 25 23 F L541P/A1038V F655C 14 33 M R152Q G1961E 402ins24bp 18 21 M A60V G1961E 15 23 M G690V A1598D 11 27 M G1961E R2149X 11 51 F V615A G1961E 25 54 M N96D N1436I 28 21 M 250insCAAA P402A 13 25 F R1448K c.5018&#fe;2T>C 21 49 M 4538insC IVS40&#fe;5G>A 18 23 F G1961E c.6282&#fe;1G>C 18 46 M N96D N1436I 30 T ABLE 4. Login to comment

PMID: 26593885 [PubMed] Sciezynska A et al: "Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe."

No. Sentence Comment

9 [(L541P; A1038V)] complex allele, which represents an unusually high level of genetic homogeneity for ABCA4-related diseases. Login to comment
12 [(L541P; A1038V)] and/or a truncating ABCA4 mutation always resulted in an early disease onset. Login to comment
74 [(L541P; A1038V)] was performed by BresloweDay test and Tarone's test implemented in the SPSS software package (SPSS Inc. Chicago, IL, USA). Login to comment
85 Using a statistical approach we compared the OR for STGD associated with the p.V552I (ORp.V552I) with the ORp.[(L541P;A1038V)], conferred by a well-established pathogenic variant p. Login to comment
86 [(L541P; A1038V)] (see Section 3.2). Login to comment
87 As we calculated, ORp.V552I &#bc; 1.08 with 95% confidence intervals (CI) from 0.24 to 4.85, while ORp.[(L541P;A1038V)] &#bc; 59.05 with CI from 22.85 to 152.61. Login to comment
89 The statistical significance of the difference between ORp.V552I and ORp.[(L541P;A1038V)] is further supported by BresloweDay test (p &#bc; 5.87E-08) and Tarone's test (p &#bc; 6.02E-08). Login to comment
92 Identification of complex alleles and common ABCA4 mutations The most frequent ABCA4 mutation detected in more than 35% (33/92) of our patients was p.L541P. Login to comment
95 [(L541P; A1038V)] complex allele is well established, co-occurrence of both changes within one haplotype has been verified for selected cases, in which family samples were available for the study. Login to comment
124 [(L541P; A1038V)] correlated with AO in the direction unexpected for a non-truncating variant (Spearman R &#bc; 0.24, p &#bc; 0.019), suggesting that the effect of p. Login to comment
125 [(L541P; A1038V)] was a strong one, more similar to truncating than the non-truncating variants. Login to comment
127 [(L541P; A1038V)] thus creating a group of "strong" mutations. Login to comment
130 [(L541P; A1038V)] is shown in Fig. 2. Login to comment
139 [(L541P; A1038V)] allele, was present in more than 33.7% (31/92) of our patients, which corresponds to at least one fourth (37/143) of all alleles with an identified mutation. Login to comment
141 [(L541P; A1038V)] allele frequency of 20.1% (37/184) in our cohort is higher than the 14% (10/70) reported in Hungarian Table 1 Frequency of common ABCA4 variant alleles identified in the study compared with control subjects of European origin. Login to comment
147 [(L541P; A1038V)] (37/184) (5/1178) p < 0.0001 c. Login to comment
158 [(L541P; A1038V)] has been so far regarded as a founder mutation of mostly German origin (Hargitai et al., 2005; Rivera et al., 2000). Login to comment
160 [(L541P; A1038V)] allele among our patients was paralleled by a relatively high frequency of p.L541P- and p.A1038V-containing alleles in the Polish population. Login to comment
161 To dissect the pathogenic potential of p.L541P and p.A1038V, both mutations were examined independently. Login to comment
163 Subsequent functional studies in transgenic frogs have demonstrated that the ABCA4 protein processing is affected by p.L541P but not by p.A1038V. Login to comment
164 A mislocalization of the p.L541P mutant in the rod inner segments and correct localization of p.A1038V to rod outer segments were detected. Login to comment
165 The results suggested that p.L541P is the major disease-causing mutation as it prevents the ABCA4 protein from reaching its proper physiological compartment and produces a functionally null allele (Wiszniewski et al., 2005). Login to comment
167 [(L541P; A1038V)] had a strong impact on the age of disease onset in our patients. Login to comment
170 [(L541P; A1038V)] was almost three times earlier (7.8 vs. 23.7 years) than in patients with other missense or with no detectable ABCA4 mutations (data not shown). Login to comment
193 [(L541P; A1038V)] and/or truncating mutations (standard error (SE), confidence interval (CI), number of patients (n)). Login to comment
195 [(L541P; A1038V)] and/or truncating mutations on disease age of onset (AO). Login to comment
197 [(L541P; A1038V)] and/or truncating mutations One p. Login to comment
198 [(L541P; A1038V)] and/or truncating mutations Two p. Login to comment
199 [(L541P; A1038V)] and/or truncating mutations Total no. Login to comment
210 [(L541P; A1038V)] in the German and Polish patients, and p.R1129L in the Spanish patients, the data cast considerable doubt on the pathogenic potential of p.V552I. Login to comment
214 [(L541P; A1038V)] showed a strong statistically significant difference indicating that p.V552I is either non-pathogenic or has a very low penetrance. Login to comment