ABCMdb

PMID: 23953153

Fujinami K, Sergouniotis PI, Davidson AE, Wright G, Chana RK, Tsunoda K, Tsubota K, Egan CA, Robson AG, Moore AT, Holder GE, Michaelides M, Webster AR
Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function.
Am J Ophthalmol. 2013 Sep;156(3):487-501.e1. doi: 10.1016/j.ajo.2013.05.003., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCA4 p.Arg2030Gln There was a higher prevalence of the variant p.Arg2030Gln in the cohort with foveal sparing compared to the group with foveal atrophy (6.45% vs 1.07%). Login to comment 45 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Arg2107His ABCA4 p.Arg2030Gln ABCA4 p.Arg1898His ABCA4 p.Glu471Lys ABCA4 p.Asp1532Asn 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 46 ABCA4 p.Arg2030Gln ABCA4 p.Arg602Gln 1805G>A, p. Arg602Gln/c.3898 C>T, p.Arg1300*] 6 65* 65 0.18 0 1 211 187 U 1 N N NA NA [c.5461-10 T>C, Splice site/c. 6089 G>A, p.Arg2030Gln] 7 54* 54 0 0 1 189 198 1 A A NA NA [c. Login to comment 47 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg1640Trp ABCA4 p.Arg1640Trp ABCA4 p.Cys1490Tyr ABCA4 p.Arg653Cys ABCA4 p.Thr1526Met ABCA4 p.Arg2030Gln ABCA4 p.Arg1898His ABCA4 p.Trp1408Arg ABCA4 p.Trp1408Arg ABCA4 p.Asp1532Asn ABCA4 p.Arg24His 6089 G>A, p.Arg2030Gln/c.6118 C>T, p.Arg2040*] 8 39 44 0.1 0.1 4 297 230 U 3 A A NA NA [c.71 G>A, p.Arg24His/c.4577 C>T, p. Thr1526Met] 9 35* 35 0.18 0.18 2 142 154 3 ND ND NA NA [c.658 C>T, p.p.Arg220Cys/c.2588 G>C, p. Gly863Ala] 10 45 54 0.48 0.18 1 102 116 3 ND A NA NA [c.1957 C>T, p.Arg653Cys/c.5693 G>A, p.Arg1898His] 11 43 43 0.1 0 2 170 185 1 A A 2 2 [c.2588 G>C, p. Gly863Ala/c.4139 C>T, p.Ala1038Val] 12 36** 38 0.3 0 1 220 212 U 1 A A 1 1 [c.4139 C>T, p.Ala1038Val/c.4594 G>T, p.Asp1532Asn] 13 62 68 0.1 0.48 1 196 189 U 1 N N 2 2 [c.4222 T>C, p.Trp1408Arg/c.4918 C>T, p.Arg1640Trp] 14 36 44 0.48 0.48 3 79 89 1 A A NA NA [c.4222 T>C, p.Trp1408Arg/c.4918 C>T, p.Arg1640Trp] 15 46* 46 0.1 0.1 3 NA NA 1 A A NA NA [c.4469 G>A, p.Cys1490Tyr/c. Login to comment 48 ABCA4 p.Gly1961Glu ABCA4 p.Gly863Ala ABCA4 p.Arg653Cys ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Ile1562Thr ABCA4 p.Arg2030Gln ABCA4 p.Leu1201Arg ABCA4 p.Leu1201Arg ABCA4 p.Ser1642Arg ABCA4 p.Phe1440Ser ABCA4 p.Arg602Gln 6089 G>A, p.Arg2030Gln] 16 44* 44 0.18 0 2 NA NA 1 A A NA NA [c.6079 C>T, p.Leu2027Phe/c.6079 C>T, p.Leu2027Phe] 17 48 73 0.18 3 4 135 86 U 2 A ND NA NA [c.4956 T>G, p.Tyr1652*] 18 56 57 0 0 2 254 273 1 ND A NA NA [c.5018&#fe;2 T>C, Splice site] 19 53* 53 0.48 0.18 1 137 133 1 A A NA NA [c.5461-10 T>C, Splice site] 20 49 58 0.18 0 1 256 222 U 1 A N 1 1 [c.5461-10 T>C, Splice site] 21 47** 47 0.3 0.3 1 239 202 U 1 A A 1 1 [c.1805 G>A, p.Arg602Gln] 22 50* 50 0.48 0.18 1 263 261 U 1 N N NA NA [c.1957 C>T, p.Arg653Cys] 23 39* 39 0 0.1 2 225 228 1 N N NA NA [c.2588 G>C, p. Gly863Ala] 24 55 57 0.48 0.48 1 117 74 1 ND ND NA NA [c.3602 T>G, p.Leu1201Arg] 25 50 54 0.48 0.18 1 147 144 U 3 ND ND NA NA [c.3602 T>G, p.Leu1201Arg] 26 43 47 2 0.18 1 70 52 1 ND ND NA NA [c.4319 T>C, p.Phe1440Ser] 27 30 51 0.3 0.3 1 75 79 U 3 A A NA NA [c.4685 T>C, p.Ile1562Thr] 28 29 34 0.18 0.18 3 132 107 1 A A NA NA [c.4926 C>G, p.Ser1642Arg] 29 52* 52 0.18 0.18 3 180 200 1 ND ND 2 2 [c.5882 G>A, p.Gly1961Glu] 30 28 28 0.1 0.1 2 NA NA 1 N ND NA NA [c.6079 C>T, p.Leu2027Phe] 31 40* 40 0.1 0.1 2 222 223 U NA NA NA NA NA [c.6079 C>T, p.Leu2027Phe] 32 45 48 0.18 3 1 237 252 U NA NA NA NA NA NA Continued on next page Tartu, Estonia) in all probands.43 The term ''variants`` used herein includes those sequence changes previously shown to be enriched in patients with Stargardt disease from prior studies. Login to comment 126 ABCA4 p.Leu541Pro ABCA4 p.Arg653Cys ABCA4 p.Arg602Gln ABCA4 p.Glu471Lys ABCA4 p.Arg220Cys ABCA4 p.Arg24His 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 127 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Arg2107His ABCA4 p.Arg1640Trp ABCA4 p.Cys1490Tyr ABCA4 p.Leu2027Phe ABCA4 p.Ile1562Thr ABCA4 p.Thr1526Met ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu ABCA4 p.Arg1898His ABCA4 p.Leu1201Arg ABCA4 p.Ser1642Arg ABCA4 p.Phe1440Ser ABCA4 p.Trp1408Arg ABCA4 p.Asp1532Asn 2588G>C, p.Gly863Ala 4 Het Allikmets46 Intol. 0.01 PRD 0.996 No change 68/13006 db SNP (rs76157638) 21 c.3113C>T, p.Ala1038Val 1 Het Webster53 Tol. NA Benign 0.014 Donor 43.5 70 New site (&#fe;61.72) 22/13006 db SNP (rs61751374) 24 c.3602T>G, p.Leu1201Arg 2 Het Lewis48 Tol. NA Benign 0.052 Donor 61.3 74 New site (&#fe;20.08) 416/13006 db SNP (rs61750126) 27 c.3898C>T, p.Arg1300* 1 Het Rivera49 NA NA ND 28 c.4139C>T, p.Pro1380Leu 2 Het Lewis48 Intol. 0.01 Benign 0.377 No change 2/13006 db SNP (rs61750130) 28 c.4222 T>C, p.Trp1408Arg 2 Het Lewis48 Tol. NA PRD 0.845 No change ND dbSNP (rs61750135) 29 c.4319T>C, p.Phe1440Ser 1 Het Lewis48 Tol. NA PRD 0.744 No change ND dbSNP (rs61750141) 30 c.4469G>A, p.Cys1490Tyr 1 Het Webster53 Intol. 0.03 PRD 0.994 No change ND dbSNP (rs61751402) 31 c.4577C>T, p.Thr1526Met 1 Het Lewis48 Intol. 0.00 PRD 0.91 No change ND db SNP (rs61750152) 31 c.4594G>T, p.Asp1532Asn 3 Het Lewis48 Tol. NA PRD 0.853 No change ND 33 c.4685T>C, p.Ile1562Thr 1 Het Allikmets46 Tol. NA Benign 0.034 No change 18/13006 db SNP (rs1762111) 35 c.4956T>G, p.Tyr1652* 1 Het Fumagalli52 NA NA Acceptor 43 72 New site (&#fe;67.36) ND 35 c.4918C>T, p.Arg1640Trp 2 Het Rozet47 Intol. 0.00 PRD 1 No change ND dbSNP (rs61751404) 35 c.4926C>G, p.Ser1642Arg 1 Het Birch50 Tol. 0.68 Benign 0.116 No change ND db SNP (rs61753017) Int 35 c.5018&#fe;2T>C, Splice site 1 Het Fumagalli52 NA NA Donor 81.2 54 WT site broken (33.07) ND Int 38 c.5461-10T>C 3 Het Briggs50 NA NA No change 3/13006 db SNP (rs1800728) 40 c.5693G>A, p.Arg1898His 2 Het Allikmets46 NA Benign 0.00 No change 25/13006 db SNP (rs1800552) 42 c.5882G>A, p.Gly1961Glu 1 Het Allikmets46 Tol. 0.18 PRD 1 No change 41/13006 db SNP (rs1800553) 44 c.6079C>T, p.Leu2027Phe 4 Homo Lewis48 Intol. 0.02 PRD 0.999 No change 4/13006 db SNP (rs61751408) 44 c.6089G>A, p.Arg2030Gln 4 Het Lewis48 Tol. NA PRD 0.995 No change 8/13006 db SNP (rs61750641) 44 c.6118C>T, p.Arg2040* 1 Het Rosenberg54 NA NA ND 46 c.6320G>A, p.Arg2107His 1 Het Fishman8 Intol. 0.00 PRD 0.996 No change 91/13006 db SNP (rs62642564) EVS &#bc; Exome Variant Server; HSF &#bc; Human Splicing Finder program; Hum var score &#bc; Human var score; Int &#bc; intron; Intol &#bc; intolerant; Mt CV &#bc; mutant consensus value; NA &#bc; not applicable; ND &#bc; not detected; PRD &#bc; probably damaging; Pred. &#bc; prediction; SIFT &#bc; Sorting Intolerant from Tolerance program; Tol. &#bc; tolerant; Wt CV &#bc; wild-type consensus value. Login to comment 136 ABCA4 p.Gly863Ala ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln The most common variants identified were p.Gly863Ala, c.5461-10T>C, p.Leu2027Phe, and p.Arg2030Gln, occurring, respectively, in 4, 3, 3, and 4 patients with the foveal-sparing phenotype of Stargardt disease. Login to comment 137 ABCA4 p.Leu2027Phe One patient was identified to be homozygous for the p.Leu2027Phe variant; none had 2 or more null variants. Login to comment 140 ABCA4 p.Gly863Ala The 4 most prevalent variants were p.Gly863Ala, TABLE 3. Login to comment 141 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Thr1019Met ABCA4 p.Cys1488Arg ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys75Gly ABCA4 p.Arg602Trp ABCA4 p.Asn965Ser ABCA4 p.Arg653Cys ABCA4 p.Arg1098Cys ABCA4 p.Thr1526Met ABCA4 p.Arg1108Cys ABCA4 p.Pro1380Leu ABCA4 p.Thr901Ala ABCA4 p.Leu1201Arg ABCA4 p.Gly991Arg ABCA4 p.Glu1087Lys ABCA4 p.Val931Met ABCA4 p.Arg152Gln ABCA4 p.Phe1440Ser ABCA4 p.Trp1408Arg ABCA4 p.Lys346Thr ABCA4 p.Glu1122Lys ABCA4 p.Arg219Thr ABCA4 p.Ile156Val ABCA4 p.Arg1108His ABCA4 p.Glu1022Lys ABCA4 p.Cys641Ser ABCA4 p.Thr1572Met ABCA4 p.Thr1428Met ABCA4 p.Arg1129His ABCA4 p.Arg24His ABCA4 p.Gly606Asp 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 142 ABCA4 p.Gly1961Glu ABCA4 p.Arg2107His ABCA4 p.Leu1970Phe ABCA4 p.Arg1640Trp ABCA4 p.Val2050Leu ABCA4 p.Leu2027Phe ABCA4 p.Ala1598Asp ABCA4 p.Arg2030Gln ABCA4 p.Arg1705Gln ABCA4 p.Cys2150Tyr ABCA4 p.Glu2096Lys 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) (Continued) Exon Nucleotide Substitution and Amino Acid Change Number of Alleles Allele Frequency Int 33 c.4773&#fe;48C>T 1 0.36% 34 c.4793C>A, p.Ala1598Asp 1 0.36% 35 c.c.4918C>T, p.Arg1640Trp 1 0.36% Int 35 c.5018&#fe;2T>C, Splice site 2 0.71% 36 c.5114G>A, p.Arg1705Gln 2 0.71% 37 c.5222_5233delTGGTGGTGGGC, p.Lys1741Hisfs 1 0.36% 37 c.5281_5289delCTT CCT GCC, p.Pro1761_Leu1763del 2 0.71% Int 38 c.5461-10T>C 23 8.21% Int 39 c.5585-1G>A, Splice site 1 0.36% Int 40 c.5714&#fe;5G>A, Splice site 5 1.79% 42 c.5882G>A, p.Gly1961Glu 17 6.07% 43 c.5908C>T, p.Leu1970Phe 2 0.71% 43 c.5917delG, p.Val1973* 1 0.36% 44 c.6079C>T, p.Leu2027Phe 10 3.57% 44 c.6089G>A, p.Arg2030Gln 3 1.07% 44 c.6118C>T, p.Arg2040* 1 0.36% 45 c.6148G>C, p.Val2050Leu 3 1.43% 46 c.6286G>A, p.Glu2096Lys 1 0.36% 46 c.6320G>A, p.Arg2107His 4 1.43% 47 c.6445C>T, p.Arg2149* 1 0.36% 47 c.6449G>A, p.Cys2150Tyr 3 1.07% 48 c.6658C>T, p.Gln2220* 3 1.07% 48 c.6709_6710insG, p.Thr2237Serfs 1 0.36% Int &#bc; Intron. Login to comment 145 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu p. Pro1380Leu, c.5461-10T>C, and p.Gly1961Glu, occurring in 19, 14, 23, and 17 patients, respectively. Login to comment 146 ABCA4 p.Arg2030Gln Sequence variant frequencies were compared between the 2 groups of patients and there was a suggestion of a higher frequency of the variant p.Arg2030Gln in the cohort with the foveal-sparing phenotype compared to the group with typical Stargardt disease (Table 4). Login to comment 160 ABCA4 p.Gly1961Glu ABCA4 p.Arg2030Gln Thirty likely disease-causing variants were identified in 31 patients, including 29 previously reported disease-causing variants and the 1 novel putative disease-causing splice site variant, c.1760&#fe;1G>T.8,20,46-54 Interestingly, there was a suggestion of a higher frequency of the substitution p.Arg2030Gln in the foveal-sparing cohort (incidence ratio: 6.5% for the foveal-sparing phenotype and 1.1% for typical Stargardt), with a possible lower incidence of p.Gly1961Glu in the foveal-sparing cohort (incidence ratio: 1.6% for the foveal-sparing phenotype and 6.1% for typical Stargardt). Login to comment 164 ABCA4 p.Gly1961Glu ABCA4 p.Gly863Ala ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu Comparison of the Most Prevalent ABCA4 Variants` Frequency Between the Cohort With the Foveal-Sparing Stargardt Disease and the Group With the Typical Stargardt Disease (Without Evidence of Foveal Sparing) Number of Alleles and Those Frequencies Foveal-Sparing Stargardt Disease (n &#bc; 31, Total 30 Variants in 62 Alleles) Typical Stargardt Disease (n &#bc; 140, Total 72 Variants in 280 Alleles) c.2588G>C, p.Gly863Ala 4 (6.45%) 19 (6.79%) c.4139C>T, p.Pro1380Leu 2 (3.23%) 14 (5.00%) c.6079C>T, p.Leu2027Phe 4 (6.45%) 10 (3.57%) c.6089G>A, p.Arg2030Gln 4 (6.45%) 3 (1.07%) c.5461-10T>C 3 (4.84%) 23 (8.21%) c.5882G>A, p.Gly1961Glu 1 (1.61%) 17 (6.07%) in the foveal-sparing phenotype compared to the typical phenotype; there was also clear concordance in sibships with the foveal-sparing phenotype, although a possible influence of genetic/environmental modifiers cannot be excluded. 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