ABCA4 p.Asp576His
| Predicted by SNAP2: | A: D (53%), C: D (53%), E: N (78%), F: D (66%), G: N (57%), H: N (53%), I: D (59%), K: N (57%), L: D (66%), M: D (63%), N: N (61%), P: N (53%), Q: N (57%), R: N (53%), S: N (66%), T: N (72%), V: D (53%), W: D (80%), Y: D (63%), |
| Predicted by PROVEAN: | A: D, C: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Molecular testing for hereditary retinal disease a... Arch Ophthalmol. 2007 Feb;125(2):252-8. Downs K, Zacks DN, Caruso R, Karoukis AJ, Branham K, Yashar BM, Haimann MH, Trzupek K, Meltzer M, Blain D, Richards JE, Weleber RG, Heckenlively JR, Sieving PA, Ayyagari R
Molecular testing for hereditary retinal disease as part of clinical care.
Arch Ophthalmol. 2007 Feb;125(2):252-8., [PMID:17296903]
Abstract [show]
OBJECTIVE: To describe clinical molecular testing for hereditary retinal degenerations, highlighting results, interpretation, and patient education. METHODS: Mutation analysis of 8 retinal genes was performed by dideoxy sequencing. Pretest and posttest genetic counseling was offered to patients. The laboratory report listed results and provided individualized interpretation. RESULTS: A total of 350 tests were performed. The molecular basis of disease was determined in 133 of 266 diagnostic tests; the disease-causing mutations were not identified in the remaining 133 diagnostic tests. Predictive and carrier tests were requested for 9 and 75 nonsymptomatic patients with known familial mutations, respectively. CONCLUSIONS: Molecular testing can confirm a clinical diagnosis, identify carrier status, and confirm or rule out the presence of a familial mutation in nonsymptomatic at-risk relatives. Because causative mutations cannot be identified in all patients with retinal diseases, it is essential that patients are counseled before testing regarding the benefits and limitations of this emerging diagnostic tool. CLINICAL RELEVANCE: The molecular definition of the genetic basis of disease provides a unique adjunct to the clinical care of patients with hereditary retinal degenerations.
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86 Novel Sequence Changes Gene* Nucleotide Change Amino Acid Change Potentially Pathogenic Changes ABCA4 164A → C H55P 611G → A A204T 868C → T R290W 1699G → A V567M 1726G ș2; C D576H 1817G → A G606A 1964T → G L725I 2173C → A F655C 2297G → A G766D 2385C → G S795R 2401G→ A A801T 3076T → C F1026L 3138T → G L1046W 3414T → C L1138P 4256T → C M1419T 4535C → A P1512H 4849G → A V1617M 4870T → G W1624G 5026A → C T1676P IVS36 - 3G→ C Splice site change 5701C → A F1900L 5885T → A V1962D 6718A → G T2240A IVS42 ϩ 1G → A Intronic change RDS 667G → C C222S VMD2 174A → G Y29C 660T → C L191P 738G → T L217F 948G → A W287X 974A → G N296D Potentially Neutral Polymorphic Changes or Changes of Uncertain Significance ABCA4 320C → A R107R 1692A → G P562P 2823T → C C941C 4869C → G G1623G 5318C → T A1773V† 5390T → C C1797C IVS15 - 13T → C Intronic change IVS24 ϩ 46A → T Intronic change IVS35 ϩ 8G → A Intronic change IVS40 - 35A → C Intronic change IVS47 ϩ 29T → C Intronic change IVS50 - 131ins/del Intronic change EFEMP1 399C → A G133G RDS IVS3 ϩ 13C → T Intronic change *The genes are described in the second footnote to Table 1.
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ABCA4 p.Asp576His 17296903:86:202
status: NEW[hide] Detection rate of pathogenic mutations in ABCA4 us... Arch Ophthalmol. 2012 Nov;130(11):1486-90. doi: 10.1001/archophthalmol.2012.1697. Downes SM, Packham E, Cranston T, Clouston P, Seller A, Nemeth AH
Detection rate of pathogenic mutations in ABCA4 using direct sequencing: clinical and research implications.
Arch Ophthalmol. 2012 Nov;130(11):1486-90. doi: 10.1001/archophthalmol.2012.1697., [PMID:23143460]
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41 Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients (continued) Subject No. Change 1 Change 2 Phase Segregation Age at Onset, y Phenotype Grade, Macula Flecks/ Cones/Rodsa Additional Variants Conclusion Nucleotide Amino Acid Nucleotide Amino Acid 48 NA NA NA NA NA NA 16 Vitelliform (historical diagnosis of STGD) maf9;af9;/0/1 0 0 PVs 49 5461-10Tb0e;C Disease-associated allele, unknown mechanism 1726Gb0e;C D576H NA NA 50 Pattern dystrophy (historical diagnosis of STGD) maf9;af9;/1/2 0 1 Splice and 1 uncertain 50 NA NA NA NA NA Unaffected sibling 45 Atypical pattern dystrophy (historical diagnosis of STGD) maf9;af9;/0/0 0 0 PVs Abbreviations: BEM, bull`s-eye maculopathy; CRA, chorioretinal atrophy; NA, not applicable; NK, not known; NP, not performed; PV, pathogenic variant; RP, retinitis pigmentosa; STGD, Stargardt disease. aThe presence of flecks at the macula was classified as follows: m indicates flecks confined to the macula; maf9;, sparse flecks extending beyond the arcades; and maf9;af9;, more extensive flecks outside the arcades. Cone and rod function was based on International Society for Clinical Electrophysiology of Vision electrophysiology including rod, standard bright white flash, cone flicker, and photopic electroretinograms. These were graded as follows: 0 indicates unaffected; 1, mild; 2, moderate; 3, moderately severe; and 4, severe. bNovel mutation. Susan M. Downes, MBChB, MD, FRCOphth Emily Packham, DipRCPath Treena Cranston, BSc, DipRCPath Penny Clouston, PhD, FRCPath Anneke Seller, PhD, DipRCPath Andrea H. Ne &#b4;meth, BSc, MBBS, DPhil, FRCP ARCH OPHTHALMOL/VOL 130 (NO. 11), NOV 2012 WWW.ARCHOPHTHALMOL.COM 1489 lopathy is genetically heterogeneous. A total of 10 novel mutations were identified (Table).
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ABCA4 p.Asp576His 23143460:41:440
status: NEW52 Table. Results From Direct Sequencing of the ABCA4 Gene in 50 Patients (continued) Subject No. Change 1 Change 2 Phase Segregation Age at Onset, y Phenotype Grade, Macula Flecks/ Cones/Rodsa Additional Variants Conclusion Nucleotide Amino Acid Nucleotide Amino Acid 48 NA NA NA NA NA NA 16 Vitelliform (historical diagnosis of STGD) maf9;af9;/0/1 0 0 PVs 49 5461-10Tb0e;C Disease-associated allele, unknown mechanism 1726Gb0e;C D576H NA NA 50 Pattern dystrophy (historical diagnosis of STGD) maf9;af9;/1/2 0 1 Splice and 1 uncertain 50 NA NA NA NA NA Unaffected sibling 45 Atypical pattern dystrophy (historical diagnosis of STGD) maf9;af9;/0/0 0 0 PVs Abbreviations: BEM, bull`s-eye maculopathy; CRA, chorioretinal atrophy; NA, not applicable; NK, not known; NP, not performed; PV, pathogenic variant; RP, retinitis pigmentosa; STGD, Stargardt disease. aThe presence of flecks at the macula was classified as follows: m indicates flecks confined to the macula; maf9;, sparse flecks extending beyond the arcades; and maf9;af9;, more extensive flecks outside the arcades. Cone and rod function was based on International Society for Clinical Electrophysiology of Vision electrophysiology including rod, standard bright white flash, cone flicker, and photopic electroretinograms. These were graded as follows: 0 indicates unaffected; 1, mild; 2, moderate; 3, moderately severe; and 4, severe. bNovel mutation. Susan M. Downes, MBChB, MD, FRCOphth Emily Packham, DipRCPath Treena Cranston, BSc, DipRCPath Penny Clouston, PhD, FRCPath Anneke Seller, PhD, DipRCPath Andrea H. Ne &#b4;meth, BSc, MBBS, DPhil, FRCP ARCH OPHTHALMOL/VOL 130 (NO. 11), NOV 2012 WWW.ARCHOPHTHALMOL.COM 1489 (c)2012 American Medical Association. All rights reserved. Downloaded From: http://archopht.jamanetwork.com/ by a Semmelweis University Budapest User on 12//2015 .
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ABCA4 p.Asp576His 23143460:52:440
status: NEW[hide] ABCA4 gene screening by next-generation sequencing... Invest Ophthalmol Vis Sci. 2013 Oct 11;54(10):6662-74. doi: 10.1167/iovs.13-12570. Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, Tsubota K, Webster AR, Moore AT, Allikmets R, Michaelides M
ABCA4 gene screening by next-generation sequencing in a British cohort.
Invest Ophthalmol Vis Sci. 2013 Oct 11;54(10):6662-74. doi: 10.1167/iovs.13-12570., [PMID:23982839]
Abstract [show]
PURPOSE: We applied a recently reported next-generation sequencing (NGS) strategy for screening the ABCA4 gene in a British cohort with ABCA4-associated disease and report novel mutations. METHODS: We identified 79 patients with a clinical diagnosis of ABCA4-associated disease who had a single variant identified by the ABCA4 microarray. Comprehensive phenotypic data were obtained, and the NGS strategy was applied to identify the second allele by means of sequencing the entire coding region and adjacent intronic sequences of the ABCA4 gene. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis. RESULTS: Of the 42 variants detected by prescreening with the microarray, in silico analysis suggested that 34, found in 66 subjects, were disease-causing and 8, found in 13 subjects, were benign variants. We detected 42 variants by NGS, of which 39 were classified as disease-causing. Of these 39 variants, 31 were novel, including 16 missense, 7 splice-site-altering, 4 nonsense, 1 in-frame deletion, and 3 frameshift variants. Two or more disease-causing variants were confirmed in 37 (47%) of 79 patients, one disease-causing variant in 36 (46%) subjects, and no disease-causing variant in 6 (7%) individuals. CONCLUSIONS: Application of the NGS platform for ABCA4 screening enabled detection of the second disease-associated allele in approximately half of the patients in a British cohort where one mutation had been detected with the arrayed primer extension (APEX) array. The time- and cost-efficient NGS strategy is useful in screening large cohorts, which will be increasingly valuable with the advent of ABCA4-directed therapies.
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55 1 c.161G>A p.C54Y DC c.2297G>T p.G766V DC 2 2 c.223T>G p.C75G DC c.5088C>G p.S1696R DC 2 3 c.740A>C p.N247T DC c.1433T>C p.I478T B c.2345G>A p.W782* DC 2 4 c.768G>T Splice site DC 1 5 c.1222C>T p.R408* DC c.2568C>A p.Y856* DC 2 6 c.1804C>T p.R602W DC c.859-9T>C Splice site PDC 2 7 c.1805G>A p.R602Q DC c.5113C>T p.R1705W DC 2 8 c.1922G>C p.C641S DC 1 9 c.1957C>T p.R653C DC 1 10 c.1957C>T p.R653C DC 1 11 c.2588G>C p.G863A DC c.655A>T p.R219* DC 2 Allele 2 (p.R219*) was APEX-false-negative 12 c.2588G>C p.G863A DC c.1906C>T p.Q636* DC 2 13 c.2588G>C p.G863A DC c.1906C>T p.Q636* DC 2 14 c.2588G>C p.G863A DC 1 15 c.2588G>C p.G863A DC 1 16 c.2894A>G p.N965S DC c.3322C>T p.R1108C DC 2 Allele 2 (p.R1108C) was APEX-false-negative 17 c.3064G>A p.E1022K DC c.6729&#fe;4_&#fe;18delAGTTGGCCCTGGGGC Splice site DC 2 18 c.3064G>A p.E1022K DC 1 19 c.3208_3209insGT p.S1071fs DC c.2942C>T p.P981L DC c.6529G>A p.D2177N B 2 20 c.3208_3209insGT p.S1071fs DC c.1519G>T p.D507Y DC 2 21 c.3208_3209insGT p.S1071fs DC c.4634G>A p.S1545N DC 2 22 c.3208_3209insGT p.S1071fs DC 1 23 c.3292C>T p.R1098C DC c.3299T>A p.I1100N DC 2 24 c.3322C>T p.R1108C DC c.4978delC p.L1661* DC 2 25 c.3386G>A p.R1129H DC c.3208_3209insGT p.S1071fs DC c.4634G>A p.S1545N DC 3 Allele 2 (p.S1071fs) was APEX false-negative and allele 1 (p.R1129H) was NGS false-negative 26 c.4139C>T p.P1380L DC c.3191-1G>T Splice site DC 2 27 c.4139C>T p.P1380L DC c.3398T>C p.I1133T PDC 2 28 c.4139C>T p.P1380L DC c.4070C>A p.A1357E DC 2 29 c.4139C>T p.P1380L DC c.4773G>C Splice site DC 2 30 c.4139C>T p.P1380L DC 1 31 c.4139C>T p.P1380L DC 1 32 c.4139C>T p.P1380L DC 1 33 c.4234C>T p.Q1412* DC 1 34 c.4319T>C p.F1440S DC 1 35 c.4328G>A p.R1443H DC c.180delG p.M61fs DC 2 36 c.4469G>A p.C1490Y DC c.1726G>C p.D576H DC 2 37 c.4469G>A p.C1490Y DC 1 38 c.4537_4538insC p.Q1513fs DC c.5578C>T p.R1860W DC 2 Allele 1 (p.Q1513fs) was NGS-false-negative 39 c.4577C>T p.T1526M DC 1 T ABLE 2. Continued Pt Allele 1 Detected by APEX Allele 2 Detected by NGS Allele 3 Detected by NGS Total N of DC Variants Comments DNA Change Protein Change/ Effect Pred. Patho. DNA Change Protein Change/ Effect Pred. Patho. DNA Change Protein Change/ Effect Pred. Patho.
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ABCA4 p.Asp576His 23982839:55:1758
status: NEW62 Hum Var Score (0-1) Site Wt CV Mt CV CV % Variation 3 c.161G>A p.C54Y 1 1 [ [ Lewis RA, et al. 11 Tol. 0.11 PRD 0.994 No change 1/13006 db SNP (rs150774447) 3 c.223T>G p.C75G 1 2 [ [ Lewis RA, et al. 11 Del. NA POD 0.603 No change ND 5 c.466A>G p.I156V 2 77, 78 [ [ Papaioannou M, et al. 16 Tol. 0.46 B 0.003 No change 16/13006 db SNP (rs112467008) Benign 6 c.655A>T p.R219* 1 11 [ Xi Q, et al. 27 ND 6 c.740A>C p.N247T 1 3 [ [ APEX Del. NA B 0.135 No change ND 6 c.768G>T Splice site 1 4 [ [ Klevering BJ, et al. 22 Tol. 0.56 NA Don. 70.4 58 Site broken (17.51) ND 9 c.1222C>T p.R408* 1 5 [ [ Webster AR, et al. 7 ND 12 c.1726G>C p.D576H 1 36 [ Downs K, et al. 25 POD 0.688 Acc. 68.1 39.1 Site broken (42.54) 1/13006 13 c.1804C>T p.R602W 1 6 [ [ Lewis RA, et al. 11 Del. 0.00 B 0.129 No change ND db SNP (rs 6179409) 13 c.1805G>A p.R602Q 1 7 [ [ Webster AR, et al. 7 Del. 0.04 PRD 0.513 Acc. 48.9 77.9 New site (&#fe;59.14) 2/13006 db SNP (rs61749410) 13 c.1906C>T p.Q636* 3 12, 13, 60 [ Zernant J, et al. 5 No change 1/13006 db SNP (rs145961131) 13 c.1922G>C p.C641S 1 8 [ [ Stenirri S, et al. 24 Del. 0.00 No change ND db SNP (rs61749416) 14 c.1957C>T p.R653C 2 9, 10 [ [ Rivera A, et al. 17 Del. 0.00 PRD 0.999 No change ND db SNP (rs61749420) 17 c.2588G>C p.G863A/ p.DelG863 5 11, 12, 13, 14, 15 [ [ Lewis RA, et al. 11 / Maugeri A, et al. 29 Del. 0.00 PRD 0.996 No change 68/13006 db SNP (rs76157638) 18 c.2701A>G p.T901A 1 74 [ [ APEX Tol. 0.82 B 0.008 23/13006 db SNP (rs139655975) Benign 19 c.2894A>G p.N965S 1 16 [ [ Lewis RA, et al. 11 Del. 0.03 PRD 0.981 Acc. 53.4 82.3 New site (&#fe;54.26) ND db SNP (rs201471607) 20 c.2971G>C p.G991R 1 67 [ [ Yatsenko AN, et al. 13 Del. 0.02 PRD 0.999 No change 28/13006 db SNP (rs147484266) Benign 22 c.3064G>A p.E1022K 2 17, 18 [ [ Webster AR, et al. 7 Del. 0.00 PRD 1.000 No change ND db SNP (rs61749459) 22 c.3208_3209insGT p.S1071fs 5 19, 20, 21, 22, 25 [ [ APEX ND False-negative in APEX in patient 25 22 c.3292C>T p.R1098C 1 23 [ [ Rivera A, et al. 17 Del. NA PRD 0.999 No change ND 22 c.3322C>T p.R1108C 3 16, 24, 61 [ [ Rozet JM, et al. 10 Del. 0.00 PRD 0.986 No change 1/13006 db SNP (rs61750120) False-negative in APEX in patients 16 and 61 23 c.3386G>A p.R1129H 1 25 [ Zernant J, et al. 5 PRD 0.989 No change ND False-negative in NGS in patient 25 24 c.3602T>G p.L1201R 4 72, 73, 74, 79 [ [ Lewis RA, et al. 11 Tol. 0.37 B 0.052 Don. 61.3 73.7 New site (20.08) 416/13006 db SNP (rs61750126) Benign 28 c.4139C>T p.P1380L 7 30, 31, 32, 33, 34, 35, 36 [ [ Lewis RA, et al. 11 Del. 0.01 B 0.377 No change 2/13006 db SNP (rs61750130) 28 c.4234C>T p.Q1412* 1 33 [ [ Rivera A, et al. 17 ND db SNP (rs61750137) 29 c.4283C>T p.T1428M 1 76 [ [ APEX Tol. 0.15 B 0.010 No change 2/13006 db SNP (rs1800549) Benign 29 c.4319T>C p.F1440S 1 34 [ [ Lewis RA, et al. 11 Del. 0.00 POD 0.744 No change ND dbSNP (rs61750141) 29 c.4326C>A p.N1442K 1 64 [ Zernant J, et al. 5 Tol. NA POD 0.374 No change ND 29 c.4328G>A p.R1443H 1 35 [ [ Rivera A, et al. 17 Del. 0.02 PRD 0.999 No change 1/13006 dbSNP (rs61750142) IVS29 c.4352&#fe;1G>A Splice site 1 73 [ Zernant J, et al. 5 Don. 82.3 55.4 WT site broken (32.62) ND 30 c.4469G>A p.C1490Y 2 36, 37 [ [ Lewis RA, et al. 11 Del. 0.00 PRD 0.994 No change ND dbSNP (rs61751402) 30 c.4538A>G p.Q1513R 1 67 [ Webster AR, et al. 7 Tol. NA Benign 0.043 Acc. 91.7 62.8 Site broken (31.55) ND T ABLE 3. Continued Exon/ IVS Nucleotide Substitution Protein Change/ Effect N of Alleles Identified Pt Method Previous Report SIFT Polyphen 2 HSF Matrix Allele Freq. by EVS Reference Comment APEX NGS Pred. Tol. Index (0-1) Pred.
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ABCA4 p.Asp576His 23982839:62:634
status: NEW