ABCMdb

PMID: 11328725

Webster AR, Heon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM
An analysis of allelic variation in the ABCA4 gene.
Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89., [PubMed]

Sentences

No. Mutations Sentence Comment

102 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Arg2107His ABCA4 p.Leu1970Phe ABCA4 p.Arg1640Trp ABCA4 p.Cys1488Arg ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys75Gly ABCA4 p.Ser100Pro ABCA4 p.Arg602Trp ABCA4 p.Asn965Ser ABCA4 p.Val2050Leu ABCA4 p.Arg2038Trp ABCA4 p.Val989Ala ABCA4 p.Arg1640Gln ABCA4 p.Leu2027Phe ABCA4 p.Val767Asp ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Cys2150Tyr ABCA4 p.Thr972Asn ABCA4 p.Thr901Ala ABCA4 p.Arg1898His ABCA4 p.Pro1948Leu ABCA4 p.Val643Met ABCA4 p.Glu1087Lys ABCA4 p.Phe1440Ser ABCA4 p.Trp1408Arg ABCA4 p.Leu2229Pro ABCA4 p.Ala192Thr ABCA4 p.Arg943Gln ABCA4 p.His423Arg ABCA4 p.Arg1129Leu ABCA4 p.Ser2255Ile ABCA4 p.Arg2077Trp ABCA4 p.Arg602Gln ABCA4 p.Phe608Ile ABCA4 p.Glu471Lys ABCA4 p.Glu1122Lys ABCA4 p.Trp1408Leu ABCA4 p.Val1433Ile ABCA4 p.Thr300Asn ABCA4 p.Gly65Glu ABCA4 p.Asn380Lys ABCA4 p.Thr971Asn ABCA4 p.Thr897Ile ABCA4 p.Arg1108His ABCA4 p.Asn1799Asp ABCA4 p.Arg220Cys ABCA4 p.Gly818Glu ABCA4 p.Val1896Asp ABCA4 p.Gly1886Glu ABCA4 p.Leu1014Arg ABCA4 p.Arg2149Leu ABCA4 p.Glu1022Lys ABCA4 p.Val849Ala ABCA4 p.Ala60Val ABCA4 p.Val1693Ile ABCA4 p.Ser1736Pro ABCA4 p.Cys764Tyr ABCA4 p.Ser206Arg ABCA4 p.Ala1637Thr ABCA4 p.Leu1250Pro ABCA4 p.Lys1031Glu ABCA4 p.Asp249Gly ABCA4 p.His2128Arg ABCA4 p.Val1884Glu ABCA4 p.Tyr1652Asp ABCA4 p.Leu1729Pro ABCA4 p.Arg2263Leu ABCA4 p.Tyr2071Phe ABCA4 p.Gln1513Arg ABCA4 p.Gly607Trp ABCA4 p.Phe873Leu ABCA4 p.Arg333Trp ABCA4 p.Thr1019Ala ABCA4 p.Pro1314Thr ABCA4 p.Leu1525Pro ABCA4 p.Ser765Asn ABCA4 p.Ser445Arg ABCA4 p.Ala854Thr ABCA4 p.Thr716Met ABCA4 p.Ser974Pro ABCA4 p.Cys1488Phe ABCA4 p.Gly851Asp ABCA4 p.Thr901Arg 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. Login to comment 103 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Arg2107His ABCA4 p.Leu1970Phe ABCA4 p.Arg1640Trp ABCA4 p.Cys1488Arg ABCA4 p.Cys54Tyr ABCA4 p.Cys1490Tyr ABCA4 p.Cys75Gly ABCA4 p.Ser100Pro ABCA4 p.Arg602Trp ABCA4 p.Asn965Ser ABCA4 p.Val2050Leu ABCA4 p.Arg2038Trp ABCA4 p.Val989Ala ABCA4 p.Arg1640Gln ABCA4 p.Leu2027Phe ABCA4 p.Val767Asp ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1486Leu ABCA4 p.Cys2150Tyr ABCA4 p.Thr972Asn ABCA4 p.Thr901Ala ABCA4 p.Arg1898His ABCA4 p.Pro1948Leu ABCA4 p.Val643Met ABCA4 p.Glu1087Lys ABCA4 p.Phe1440Ser ABCA4 p.Trp1408Arg ABCA4 p.Leu2229Pro ABCA4 p.Ala192Thr ABCA4 p.Arg943Gln ABCA4 p.His423Arg ABCA4 p.Arg1129Leu ABCA4 p.Ser2255Ile ABCA4 p.Arg2077Trp ABCA4 p.Arg602Gln ABCA4 p.Phe608Ile ABCA4 p.Glu471Lys ABCA4 p.Glu1122Lys ABCA4 p.Trp1408Leu ABCA4 p.Val1433Ile ABCA4 p.Thr300Asn ABCA4 p.Gly65Glu ABCA4 p.Asn380Lys ABCA4 p.Thr971Asn ABCA4 p.Thr897Ile ABCA4 p.Arg1108His ABCA4 p.Asn1799Asp ABCA4 p.Arg220Cys ABCA4 p.Gly818Glu ABCA4 p.Val1896Asp ABCA4 p.Gly1886Glu ABCA4 p.Leu1014Arg ABCA4 p.Arg2149Leu ABCA4 p.Glu1022Lys ABCA4 p.Val849Ala ABCA4 p.Ala60Val ABCA4 p.Val1693Ile ABCA4 p.Ser1736Pro ABCA4 p.Cys764Tyr ABCA4 p.Ser206Arg ABCA4 p.Ala1637Thr ABCA4 p.Leu1250Pro ABCA4 p.Lys1031Glu ABCA4 p.Asp249Gly ABCA4 p.His2128Arg ABCA4 p.Val1884Glu ABCA4 p.Tyr1652Asp ABCA4 p.Leu1729Pro ABCA4 p.Arg2263Leu ABCA4 p.Tyr2071Phe ABCA4 p.Gln1513Arg ABCA4 p.Gly607Trp ABCA4 p.Phe873Leu ABCA4 p.Arg333Trp ABCA4 p.Thr1019Ala ABCA4 p.Pro1314Thr ABCA4 p.Leu1525Pro ABCA4 p.Ser765Asn ABCA4 p.Ser445Arg ABCA4 p.Ala854Thr ABCA4 p.Thr716Met ABCA4 p.Ser974Pro ABCA4 p.Cys1488Phe ABCA4 p.Gly851Asp ABCA4 p.Thr901Arg 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. Login to comment 109 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile If the three most common missense variants (Asn1868Ile, Ser2255Ile, and Arg943Gln) were not included, missense variants were detected in 34 (9.3%) of 364 AMD alleles and 13 (6.7%) of 192 control alleles. Login to comment 110 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile If the three most common missense variants (Asn1868Ile, Ser2255Ile, and Arg943Gln) were not included, missense variants were detected in 34 (9.3%) of 364 AMD alleles and 13 (6.7%) of 192 control alleles. Login to comment 130 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile However, the nonconservative subset was not more strongly associated with Stargardt disease than the conservative subset, largely because three of the nonconservative changes exhibited a prevalence in non-Stargardt alleles of more than 4% (Asn1868Ile, Arg943Gln, and Ser2255Ile). Login to comment 131 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile However, the nonconservative subset was not more strongly associated with Stargardt disease than the conservative subset, largely because three of the nonconservative changes exhibited a prevalence in non-Stargardt alleles of more than 4% (Asn1868Ile, Arg943Gln, and Ser2255Ile). Login to comment 140 ABCA4 p.Pro1948Leu ABCA4 p.Ser2255Ile Two of these 13 were the common variants Ser2255Ile and Pro1948Leu. Login to comment 141 ABCA4 p.Pro1948Leu ABCA4 p.Ser2255Ile Two of these 13 were the common variants Ser2255Ile and Pro1948Leu. Login to comment 148 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Arg2107His ABCA4 p.Leu2027Phe ABCA4 p.Arg1108Cys ABCA4 p.Pro1380Leu 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 149 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Arg2107His ABCA4 p.Leu2027Phe ABCA4 p.Arg1108Cys ABCA4 p.Pro1380Leu 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 152 ABCA4 p.Pro1948Leu ABCA4 p.Arg943Gln These included two common polymorphisms Arg943Gln and Pro1948Leu that occurred on more than 3% of all alleles. Login to comment 153 ABCA4 p.Pro1948Leu ABCA4 p.Arg943Gln These included two common polymorphisms Arg943Gln and Pro1948Leu that occurred on more than 3% of all alleles. Login to comment 155 ABCA4 p.Gly863Ala ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile Three missense variants, Gly863Ala, Asn1868Ile, and Ser2255Ile, were significantly enriched among patients with Stargardt disease but not to the extent that would be expected if they were fully penetrant Stargardt alleles. Login to comment 156 ABCA4 p.Gly863Ala ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile Three missense variants, Gly863Ala, Asn1868Ile, and Ser2255Ile, were significantly enriched among patients with Stargardt disease but not to the extent that would be expected if they were fully penetrant Stargardt alleles. Login to comment 158 ABCA4 p.Gly863Ala The variant Gly863Ala occurred on 28 Stargardt alleles in 28 patients with Stargardt disease. Login to comment 160 ABCA4 p.Gly863Ala The variant Gly863Ala occurred on 28 Stargardt alleles in 28 patients with Stargardt disease. Login to comment 162 ABCA4 p.Asn1868Ile The Asn1868Ile variant was found in 71 patients with Stargardt disease and was homozygous in 8 of these. Login to comment 164 ABCA4 p.Asn1868Ile The Asn1868Ile variant was found in 71 patients with Stargardt disease and was homozygous in 8 of these. Login to comment 165 ABCA4 p.Ser2255Ile The Ser2255Ile was found in 48 patients with Stargardt disease and was homozygous in 6 of these. Login to comment 167 ABCA4 p.Ser2255Ile The Ser2255Ile was found in 48 patients with Stargardt disease and was homozygous in 6 of these. Login to comment 168 ABCA4 p.Asn1868Ile ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile The two variants Asn1868Ile and Ser2255Ile occurred together in seven patients with Stargardt disease, one being homozygous for Ser2255Ile and heterozygous for Asn1868Ile. Login to comment 169 ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile They also occurred together in one patient with AMD who was homozygous for Ser2255Ile and heterozygous for Asn1868Ile. Login to comment 170 ABCA4 p.Asn1868Ile ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile The two variants Asn1868Ile and Ser2255Ile occurred together in seven patients with Stargardt disease, one being homozygous for Ser2255Ile and heterozygous for Asn1868Ile. Login to comment 171 ABCA4 p.Asn1868Ile ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile For instance, Asn1868Ile was always associated with CTC at codon 1894 (Leu3Leu). Login to comment 172 ABCA4 p.Gly1961Glu Similarly, the Gly1961Glu variant was always associated with either of two rare alleles at codon 1948 (CCG, CTG), which in turn were always found on chromosomes bearing the common intron 41 polymorphism. Login to comment 173 ABCA4 p.Gly863Ala ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln Furthermore, the missense changes Gly863Ala and Arg943Gln were commonly found together. Login to comment 174 ABCA4 p.Gly1961Glu Similarly, the Gly1961Glu variant was always associated with either of two rare alleles at codon 1948 (CCG, CTG), which in turn were always found on chromosomes bearing the common intron 41 polymorphism. Login to comment 175 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Arg943Gln However, linkage disequilibrium was not complete, because the rarer Gly863Ala change occurred by itself in three patients with Stargardt disease. Login to comment 177 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro 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 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro One patient with Stargardt disease bore Leu541Pro without the Ala1038Val variant, and seven harbored the Ala1038Val change without Leu541Pro. Login to comment 179 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro Ala1038Val without Leu541Pro was also found in one patient with AMD. Login to comment 180 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro One patient with Stargardt disease bore Leu541Pro without the Ala1038Val variant, and seven harbored the Ala1038Val change without Leu541Pro. Login to comment 181 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Ala1038Val without Leu541Pro was also found in one patient with AMD. Login to comment 182 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro 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 184 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro 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 237 ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln For example, Arg943Gln is present in more than 6% of the normal population. If it were an HPRDCV, it alone would be expected to cause disease in more than 1 in 300 individuals, a rate that is 30 times higher than the prevalence of Stargardt disease in the population. If, on the other hand, Arg943Gln is a low-penetrance recessive DCV that is incapable of causing disease in the homozygous state but is capable of contributing to the disease phenotype when paired with certain rare HPRDCVs, this variant alone would increase our DCV detection rate by approximately 5%. Login to comment 239 ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln For example, Arg943Gln is present in more than 6% of the normal population. If it were an HPRDCV, it alone would be expected to cause disease in more than 1 in 300 individuals, a rate that is 30 times higher than the prevalence of Stargardt disease in the population. If, on the other hand, Arg943Gln is a low-penetrance recessive DCV that is incapable of causing disease in the homozygous state but is capable of contributing to the disease phenotype when paired with certain rare HPRDCVs, this variant alone would increase our DCV detection rate by approximately 5%. Login to comment 243 ABCA4 p.Gly863Ala The missense change Gly863Ala is of particular interest, because it was found in 4% of Stargardt alleles and in 0.7% of non-Stargardt alleles. Login to comment 245 ABCA4 p.Gly863Ala The missense change Gly863Ala is of particular interest, because it was found in 4% of Stargardt alleles and in 0.7% of non-Stargardt alleles. Login to comment 253 ABCA4 p.Gly1961Glu One note of caution is that a Stargardt-associated allele in one population, may no longer be in complete linkage disequilibrium with the disease in a different population, as we have recently shown for the most common change in white patients with Stargardt disease, Gly1961Glu, which appears to be quite common in normal individuals from Somalia.39 Further in vitro studies of mutated ABCA4 proteins, such as those reported by Sun et al.1 might help determine the dysfunction of, and thus the potential pathogenicity of, specific ABCA4 alleles. Login to comment 255 ABCA4 p.Gly1961Glu One note of caution is that a Stargardt-associated allele in one population, may no longer be in complete linkage disequilibrium with the disease in a different population, as we have recently shown for the most common change in white patients with Stargardt disease, Gly1961Glu, which appears to be quite common in normal individuals from Somalia.39 Further in vitro studies of mutated ABCA4 proteins, such as those reported by Sun et al.1 might help determine the dysfunction of, and thus the potential pathogenicity of, specific ABCA4 alleles. Login to comment