ABCMdb

ABCA4 p.Asn1868Ile

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Publications

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

100 In contrast, variant c.5603A>T (p.N1868I) was significantly enriched in GPS[+] and STGD1 patients, in agreement with previous findings that have led to the suggestion that the polymorphic variant c.5603A>T may act as a risk-increasing factor in ABCA4-related pathology.37 Together, these data strongly suggest that there is no founder effect in the GPS[+] group as frequencies in the common sequence variants of the ABCA4 gene are not different from the GPS[+] group and the European-American NHLBI samples. Login to comment
134 In addition, our analysis of common variant frequencies in the ABCA4 gene showed that c.5603A>T (p.N1868I) is enriched greatly in the GPS[+] group, a variant that has been suggested previously to act as a risk-increasing factor in ABCA4-related pathology.37 Our findings were in accordance with the genotype-phenotype model suggested by Maugeri et al.,7 proposing pathological effects dependent on a threshold of physiological ABCA4 activity. Login to comment
98 In contrast, variant c.5603A>T (p.N1868I) was significantly enriched in GPS[+] and STGD1 patients, in agreement with previous findings that have led to the suggestion that the polymorphic variant c.5603A>T may act as a risk-increasing factor in ABCA4-related pathology.37 Together, these data strongly suggest that there is no founder effect in the GPS[+] group as frequencies in the common sequence variants of the ABCA4 gene are not different from the GPS[+] group and the European-American NHLBI samples. Login to comment
132 In addition, our analysis of common variant frequencies in the ABCA4 gene showed that c.5603A>T (p.N1868I) is enriched greatly in the GPS[+] group, a variant that has been suggested previously to act as a risk-increasing factor in ABCA4-related pathology.37 Our findings were in accordance with the genotype-phenotype model suggested by Maugeri et al.,7 proposing pathological effects dependent on a threshold of physiological ABCA4 activity. Login to comment

PMID: 21330655 [PubMed] Aguirre-Lamban J et al: "Further associations between mutations and polymorphisms in the ABCA4 gene: clinical implication of allelic variants and their role as protector/risk factors."

No. Sentence Comment

9 The use of statistical methods showed that the frequency of the majority of polymorphisms was similar in patients and controls, except for the IVS10ϩ5delG, p.Asn1868Ile, IVS48ϩ21CϾT, and p.Arg943Gln polymorphisms. Login to comment
12 Although the high allelic heterogeneity in ABCA4 and the wide spectrum of many common and rare polymorphisms complicate the interpretation of clinical relevance, polymorphisms were identified that may act as risk factors (p.Asn1868Ile) and others that may act as protection factors (p.His423Arg and IVS10ϩ5 delG). Login to comment
76 In contrast, the p.Pro1401Pro, p.Asn1868Ile, p.Leu1894Leu, and p.Leu1938Leu variants were less frequently detected among the p.Arg1129Leu patients (Table 3). Login to comment
77 Despite this, p.His423Arg, IVS33ϩ48CϾT, p.Pro1401Pro, p.Leu1894Leu, and p.Leu1938Leu polymorphisms were detected in similar frequencies between p.Arg1129Leu patients and the control population, since no significant differences existed (P ϭ 0.108, 0.542, 0.605, 0.130, and 0.394 respectively). Login to comment
85 Most Frequent ABCA4 Polymorphisms Found in Patients and Controls Exon Nucleotide Change Amino Acid Change Patients n (%) Allele Frequency n (%) Controls n (%) Allele Frequency n (%) P - IVS48؉21C>T SPLICE 13 (10.2) 13 (5.1) 0 (0.0) 0 (0.0) 0.003 - IVS10؉5 delG SPLICE 36 (28.1) 40 (15.6) 39 (46.4) 43 (25.6) 0.006 40 c.5603A>T p.Asn1868Ile 27 (21.1) 30 (11.7) 9 (10,7) 9 (5.3) 0.049 19 c.2828GϾA p.Arg943Gln 13 (10.2) 15 (5.8) 3 (3.6) 3 (1.8) 0.076 45 c.6249CϾT p.Ile2083Ile 14 (10.9) 15 (5.8) 16 (19.0) 18 (10.7) 0.098 49 c.6764GϾT p.Ser2255Ile 13 (10.2) 13 (5.1) 15 (17.9) 16 (9.5) 0.105 10 c.1268AϾG p.His423Arg 68 (53.1) 84 (32.8) 54 (64.3) 60 (35.7) 0.108 40 c.5682GϾC p.Leu1894Leu 70 (54.7) 90 (35.1) 37 (44.0) 41 (24.4) 0.130 42 c.5843CAϾTG p.Pro1948Leu 13 (10.2) 13 (5.1) 14 (16.7) 15 (8.9) 0.164 8 c.981CϾT p.Pro327Pro 2 (1.6) 2 (0.8) 0 (0.0) 0 (0.0) 0.250 6 c.635GϾA p.Arg212His 8 (6.3) 11 (4.3) 8 (9.5) 8 (4.7) 0.377 41 c.5814AϾG p.Leu1938Leu 40 (31.3) 48 (18.7) 31 (36.9) 35 (20.8) 0.394 44 c.6069CϾT p.Ile2023Ile 17 (13.3) 17 (6.6) 14 (16.7) 15 (8.9) 0.495 IVS33ϩ48CϾT SPLICE 109 (85.2) 170 (66.4) 74 (88.1) 93 (55.3) 0.542 28 c.4203CϾA/T p.Pro1401Pro 10 (7.8) 10 (3.9) 5 (6.0) 5 (2.9) 0.605 10 c.1269CϾT p.His423His 8 (6.3) 8 (3.1) 4 (4.8) 4 (2.4) 0.647 42 c.5844AϾG p.Pro1948Pro 36 (28.1) 42 (16.4) 23 (27.4) 25 (14.9) 0.906 46 c.6285TϾC p.Asp2095Asp 39 (30.5) 43 (16.8) 25 (29.8) 27 (16.1) 0.913 Variants revealing significant differences between both groups are shown in bold. Login to comment
86 the patient group: p.Asn1868Ile (P ϭ 0.013) and p.His423Arg (P ϭ 0 0.023) (Table 3). Login to comment
87 The p.Asn1868Ile variant was found in higher proportion in patients than in control individuals (P ϭ 0.049) (Table 2) and was not present in the 82% of the carrier patients of the p.Gly1961Glu mutation (P ϭ 0.013) (Table 3). Login to comment
88 p.Arg602Trp The p.Arg602Trp mutation was found to be the third most prevalent missense variant, with a frequency of 6.3% (Table 1). Login to comment
93 This variant was significantly associated with p.His423Arg (P ϭ 0.014), p.Asn1868Ile (P Ͻ 0.001), and p.Leu1894Leu (P ϭ 0.016), as 100% of the patients carried both the mutation and these polymorphisms (Table 3). Login to comment
94 p.Arg212H is p.Pro327Pro p.H is423Arg p.H is423H is IVS10+5delG p.Arg602Trp p.Arg943G ln c.3211insG T p.Arg1129Leu p.Pro1401Pro IVS33+48C >Tp.Leu1894Leu p-Leu1938Leu p.Pro1948Leu p.Pro1948Pro p.G ly1961G lup.Leu2060Argp.Asp2095Asp IVS48+21C >T - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - p.Asn1868Ile p.Ile2023Ile p.Ile2083Ile p.Ser2255Ile PATIENTSCONTROLS FIGURE 1. Login to comment
100 Except for the IVS10ϩ5delG, p.Asn1868Ile, and IVS48ϩ21CϾT polymorphisms, the remaining polymorphic variants whose frequency was Ͼ5% failed to show any significant differences between patients and control individuals (Table 2; Fig. 1). Login to comment
102 Carriers of the T variant (homozygous and heterozygous) of p.Asn1868Ile are at more than double the risk of developing the disease than normal homozygous variant (OR: ATϩTT ϭ 2.23; 95% CI, 1.01-5.01; P ϭ 0.05; Table 4). Login to comment
109 Association between the Most Frequent ABCA4 Polymorphisms and Mutations Patients Variants Frequency P Status Predicted Effect Mutation, n (%) p.Arg1129Leu 34 (26.6) Present polymorphisms p.His423Arg 94.1% 0.000 Associated Risk IVS33؉48C>T 100% 0.011 Associated Risk IVS10ϩ5delG 20.6% 0.049 Associated Protector p.Leu1938Leu 17.6% 0.033 Associated Protector p.Ser2255Ile 2.9% 0.054 Associated Protector Mutation, n (%) p.Gly1961Glu 18 (14.1) Present polymorphisms p.Pro1948Pro 94.7% 0.000 Associated Risk p.Leu1938Leu 89.5% 0.000 Associated Risk p.Asp2095Asp 78.9% 0.000 Associated Risk IVS48؉21C>T 70.0% 0.000 Associated Risk IVS10؉5delG 57.9% 0.008 Associated Risk p.His423Arg 31.6% 0.016 Associated Protector p.Asn1868Ile 18.7% 0.039 Associated Protector Mutation, n (%) p.Arg602Trp 8 (6.3%) Present polymorphisms p.Arg943Gln 62.5% 0.000 Associated Risk p.Pro1401Pro 25% 0.044 Associated Protector p.Leu1938Leu 0% 0.041 Associated Protector Mutation, n (%) c.3211insGT 7 (5.5%) Present polymorphisms p.His423Arg 100% 0.021 Associated Risk p.Asn1868Ile 100% 0.000 Associated Risk IVS10ϩ5delG 0% 0.047 Associated Protector Mutation, n (%) p.Leu2060Arg 7 (5.5%) Present polymorphisms p.Leu1938Leu 100% 0.000 Associated Risk p.Pro1948Leu 100% 0.000 Associated Risk p.His423Arg 14.3% 0.019 Associated Protector TABLE 4. Login to comment
110 Polymorphisms and Risk of Stargardt Disease Polymorphism Genotype Cases (n ‫؍‬ 128) N Controls (n ‫؍‬ 84) N OR 95% CI P p.His423Arg AA 60 30 1 (reference) AGϩGG 68 54 0.464 0.250-0.863 0.015 IVS10ϩ5 delG Normal 92 45 1 (reference) N/DϩD/D 36 39 0.452 0.254-0.804 0.007 p.Asn1868Ile AA 101 75 1 (reference) ATϩTT 27 9 2.23 0.990-5.015 0.05 0.25-0.80; P ϭ 0.007, respectively). Login to comment
111 However, carriers of the variant sequences of the p.Asn1868Ile polymorphism exhibit a more than twofold risk of developing the disease than normal homozygous variant (OR: ATϩTT ϭ 2.23; 95% CI, 1.01-5.01; P ϭ 0.05; Table 4). Login to comment
112 Moreover, using a SIFT and a Polyphen prediction, the p.Asn1868Ile variant affected protein function. Login to comment
115 Similarly, the p.Asn1868Ile polymorphism is negatively associated with both p.Gly1961Glu and pArg1129Leu mutations and in positive association with the c.3211insGT mutation (Table 3). Login to comment
120 In a Danish population, both ABCA4 gene variants were found, though no possible association was analyzed.18 However, in a German population, 18 individuals were found to have the IVS48ϩ21CϾT polymorphism, of whom 17 had the p.Gly1961Glu mutation.15 As a contrast, p.Asn1868Ile and p.His423Arg are negatively associated with the p.Gly1961Glu mutation. Login to comment
121 p.Asn1868Ile appears at a higher frequency in patients than in controls (P ϭ 0.049), although previous studies have found the variant to occur in higher, albeit insignificant, frequency among the control population.19 The IVS10ϩ5delG polymorphism was first described in 2001 by Webster et al.18 in a study on a Danish population. Login to comment
122 We found this polymorphism, IVS10ϩ5delG, to be associated with the p.Gly1961Glu mutation (P ϭ 0.005). Login to comment
126 The p.Pro1401Pro, p.Asn1868Ile, p.Leu1894Leu, and p.Leu1938Leu polymorphisms, on the other hand, appeared less frequently among patients with the p.Arg1129Leu mutation. Login to comment
127 Except for p.Asn1868Ile, the remaining polymorphisms were found in a similar number of patients and normal control subjects (Table 2). Login to comment
129 The p.Arg943Gln polymorphism is in linkage disequilibrium with the p.Arg602Trp mutation in Spanish STGD (P Ͻ 0.001, Table 3). Login to comment
130 However, in other European studies the p.Arg943Gln variant was detected in linkage disequilibrium with the p.Gly863Ala mutation,18,19,20 and 21 but this mutation has a low frequency in our series of patients, and no association analysis was performed. Login to comment
131 This change has been described showing diminished activity of the ABCA4 protein.11,22 However, using a SIFT and a Polyphen prediction, the p.Arg943Gln variant would not affect the protein function, so it is not clear how it affects the phenotype. Login to comment
139 Except for the IVS10ϩ5delG, p.Asn1868Ile and IVS48ϩ21CϾT polymorphisms, the remaining polymorphic variants showed no significant differences between patients and control individuals. Login to comment
144 However, IVS10ϩ5delG and p.Asn1868Ile did not represent mutational hot spots. Login to comment
148 In conclusion, the p.His423Arg and IVS10ϩ5delG polymorphisms have a protective effect, whereas the p.Asn1868Ile polymorphism is a risk factor for disease. Login to comment
132 Moreover, using a SIFT and a Polyphen prediction, the p.Asn1868Ile variant affected protein function. Login to comment
135 Similarly, the p.Asn1868Ile polymorphism is negatively associated with both p.Gly1961Glu and pArg1129Leu mutations and in positive association with the c.3211insGT mutation (Table 3). Login to comment
140 In a Danish population, both ABCA4 gene variants were found, though no possible association was analyzed.18 However, in a German population, 18 individuals were found to have the IVS48af9;21Cb0e;T polymorphism, of whom 17 had the p.Gly1961Glu mutation.15 As a contrast, p.Asn1868Ile and p.His423Arg are negatively associated with the p.Gly1961Glu mutation. Login to comment
141 p.Asn1868Ile appears at a higher frequency in patients than in controls (P afd; 0.049), although previous studies have found the variant to occur in higher, albeit insignificant, frequency among the control population.19 The IVS10af9;5delG polymorphism was first described in 2001 by Webster et al.18 in a study on a Danish population. Login to comment
146 The p.Pro1401Pro, p.Asn1868Ile, p.Leu1894Leu, and p.Leu1938Leu polymorphisms, on the other hand, appeared less frequently among patients with the p.Arg1129Leu mutation. Login to comment
147 Except for p.Asn1868Ile, the remaining polymorphisms were found in a similar number of patients and normal control subjects (Table 2). Login to comment
159 Except for the IVS10af9;5delG, p.Asn1868Ile and IVS48af9;21Cb0e;T polymorphisms, the remaining polymorphic variants showed no significant differences between patients and control individuals. Login to comment
164 However, IVS10af9;5delG and p.Asn1868Ile did not represent mutational hot spots. Login to comment
168 In conclusion, the p.His423Arg and IVS10af9;5delG polymorphisms have a protective effect, whereas the p.Asn1868Ile polymorphism is a risk factor for disease. 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

83 In our series, mainly consisting of patients coming from central Italy, G1961E was the most common mutant allele, in congruence with other studies performed in distinct dissimilar European populations.9,20 Nevertheless, the frequency of G1961E mutation (20.4% of our STGD alleles) was higher than in the other Italian Table 3 Summary of the polymorphic variants identified in the ABCR gene in our series of STGD Italian patients Location Polymorphic variants Number of alleles Exon 3 IVS3 þ 26a4g 14 Exon 5 D159 1 Exon 6 R212H 6 Exon 7 IVS7-32t4c 9 Exon 10 H423R 12 Exon 13 D644 1 Exon 14 IVS14 þ 50t4c 1 Exon 15 IVS15-13t4c 2 Exon 16 IVS16-13c4t 1 Exon 19 R943Q 3 Exon 20 L1988 1 Exon 23 Q1169 4 Exon 23 IVS23 þ 25g4a 2 Exon 24 T1176 6 Exon 24 K1182 3 Exon 28 P1401 1 Exon 33 IVS33-39t4c 2 Exon 34 IVS34 þ 16insgtt 4 Exon 38 D1817Q 7 Exon 40 N1868I 3 Exon 40 L1894 16 Exon 41 L1938 15 Exon 42 P1948 23 Exon 44 I2023 5 Exon 44 IVS44-16g4a 5 Exon 44 IVS44 þ 77g4a 1 Exon 45 I2083 5 Exon 46 D2095 19 Exon 48 IVS48 þ 21c4t 3 Exon 49 S2255I 5 studies where this mutation was detected in 11.110 and 9.7% 11 of the screened alleles. Login to comment

PMID: 18977788 [PubMed] Riveiro-Alvarez R et al: "Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease."

No. Sentence Comment

96 These Table 1 ABCA4 sequence variants identified in Spanish control population Mutant alleles Nucleotide change Amino acid change Number of cases Number of alleles Frequency (%) Homozygous individuals Mutations* c.661G.A p.Gly221Arg 1 1 0.64 None c.1140T.A p.Asn380Lys 1 1 0.64 None c.2588G.C p.Gly863Ala 1 1 0.64 None c.3113C.T p.Ala1038Val 1 1 0.64 None c.3899G.A p.Arg1300Gln 1 1 0.64 None c.5882G.A p.Gly1961Glu 1 1 0.64 None c.5908C.T p.Leu1970Phe 1 1 0.64 None c.6148G.C p.Val2050Leu 1 1 0.64 None c.6529G.A p.Asp2177Asn 2 2 1.28 None Total 10 Polymorphisms{ c.466A.G p.Ile156Val 5 5 3.2 None c.635G.A p.Arg212His 5 6 3.84 1 c.1268A.G p.His423Arg 43 48 30.7 5 c.1269C.T p.His423His 2 2 1.28 None IVS10+5delG 34 36 23 2 c.2828G.A p.Arg943Gln 1 1 0.64 None c.4203C.A p.Pro1401Pro 3 3 1.9 None IVS33+48C.T 59 75 48 16 c.5603A.T p.Asn1868Ile 4 4 2.5 None c.5682G.C p.Leu1894Leu 29 35 22.4 6 c.5814A.G p.Leu1938Leu 27 33 21.1 6 c.5843 C.T p.Pro1948Leu 9 10 6.4 1 c.5844A.G p.Pro1948Pro 27 32 20.5 5 c.6069C.T p.Ile2023Ile 11 12 7.7 1 c.6249C.T p.Ile2083Ile 12 14 8.9 2 c.6285T.C p.Asp2095Asp 24 26 16.6 2 c.6764G.T p.Ser2255Ile 12 13 8.3 1 *A total of 15 mutant alleles were detected. Login to comment
97 These Table 1 ABCA4 sequence variants identified in Spanish control population Mutant alleles Nucleotide change Amino acid change Number of cases Number of alleles Frequency (%) Homozygous individuals Mutations* c.661G.A p.Gly221Arg 1 1 0.64 None c.1140T.A p.Asn380Lys 1 1 0.64 None c.2588G.C p.Gly863Ala 1 1 0.64 None c.3113C.T p.Ala1038Val 1 1 0.64 None c.3899G.A p.Arg1300Gln 1 1 0.64 None c.5882G.A p.Gly1961Glu 1 1 0.64 None c.5908C.T p.Leu1970Phe 1 1 0.64 None c.6148G.C p.Val2050Leu 1 1 0.64 None c.6529G.A p.Asp2177Asn 2 2 1.28 None Total 10 Polymorphisms{ c.466A.G p.Ile156Val 5 5 3.2 None c.635G.A p.Arg212His 5 6 3.84 1 c.1268A.G p.His423Arg 43 48 30.7 5 c.1269C.T p.His423His 2 2 1.28 None IVS10+5delG 34 36 23 2 c.2828G.A p.Arg943Gln 1 1 0.64 None c.4203C.A p.Pro1401Pro 3 3 1.9 None IVS33+48C.T 59 75 48 16 c.5603A.T p.Asn1868Ile 4 4 2.5 None c.5682G.C p.Leu1894Leu 29 35 22.4 6 c.5814A.G p.Leu1938Leu 27 33 21.1 6 c.5843 C.T p.Pro1948Leu 9 10 6.4 1 c.5844A.G p.Pro1948Pro 27 32 20.5 5 c.6069C.T p.Ile2023Ile 11 12 7.7 1 c.6249C.T p.Ile2083Ile 12 14 8.9 2 c.6285T.C p.Asp2095Asp 24 26 16.6 2 c.6764G.T p.Ser2255Ile 12 13 8.3 1 *A total of 15 mutant alleles were detected. Login to comment

PMID: 19365591 [PubMed] Maia-Lopes S et al: "ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis."

No. Sentence Comment

111 Exon Nucleotide Change Effect STGD Families Frequency References IVS3 c.302+20C>T - 12 4.8% [6] IVS3 c.302+26A>G - 7,12,13,14 1.91% [6] 6 c.635G>A p.Arg212His 13,19 9.5% [15] IVS7 c.859+8T>C - 17 4.8% Present study 10 c.1268A>G p.His423Arg 2,4,5,6,10,11,12,13,14,18,19 53% [13] 10 c.1269C>T p.His423His 16 4.8% [13] IVS10 c.1356+5delG SPLICE 1,7,11,15,20 23.8% [13] IVS14 c.2161+47T>C - 18 4.8% Present study 19 c.2828G>A p.Arg943Gln 3,10,18,19 19.1% [5] IVS19 c.2919+34C>T - 12 4.8% Present study 20 c.2964T>C p.Leu988Leu 12 4.8% [6] IVS22 c.3326-19G>A - 2 4.8% Present study IVS33 c.4773+48C>T Splice 1,2,3,5,6,8,9,10,12,13,14,16,17,18,19,20 76.2% [13] 40 c.5603A>T p.Asn1868Ile 4,10,17 14.3% [6] 40 c.5682G>C p.Leu1894Leu 1,2,4,5,8,10,12,13,17,18 47.6% [6] 41 c.5814A>G p.Leu1938Leu 1,2,5,8,10,12,13,18 3.81% [6] 42 c.5843CA>TG/c.5843C>T p.Pro1948Leu 11 4.8% [14] 42 c.5844A>G p.Pro1948Pro 1,2,5,8,10,12,13 33.3% [14] 44 c.6069C>T p.Ile2023Ile 9,12,14,19 19.1% [6] 45 c.6249C>T p.Ile2083Ile 9,12,14,19 19.1% [5] 46 c.6285T>C p.Asp2095Asp 1,2,8,9,10,12,14,19 38.1% [14] IVS48 c.6769+21C>T SPLICE 1,10 9.5% [6] 49 c.6764G>T p.Ser2255Ile 1,9,14,19 19.1% [5] Several polymorphisms in exons and introns (IVS) throughout the entire ABCA4 gene were found in our study population. Login to comment
110 Exon Nucleotide Change Effect STGD Families Frequency References IVS3 c.302+20C>T - 12 4.8% [6] IVS3 c.302+26A>G - 7,12,13,14 1.91% [6] 6 c.635G>A p.Arg212His 13,19 9.5% [15] IVS7 c.859+8T>C - 17 4.8% Present study 10 c.1268A>G p.His423Arg 2,4,5,6,10,11,12,13,14,18,19 53% [13] 10 c.1269C>T p.His423His 16 4.8% [13] IVS10 c.1356+5delG SPLICE 1,7,11,15,20 23.8% [13] IVS14 c.2161+47T>C - 18 4.8% Present study 19 c.2828G>A p.Arg943Gln 3,10,18,19 19.1% [5] IVS19 c.2919+34C>T - 12 4.8% Present study 20 c.2964T>C p.Leu988Leu 12 4.8% [6] IVS22 c.3326-19G>A - 2 4.8% Present study IVS33 c.4773+48C>T Splice 1,2,3,5,6,8,9,10,12,13,14,16,17,18,19,20 76.2% [13] 40 c.5603A>T p.Asn1868Ile 4,10,17 14.3% [6] 40 c.5682G>C p.Leu1894Leu 1,2,4,5,8,10,12,13,17,18 47.6% [6] 41 c.5814A>G p.Leu1938Leu 1,2,5,8,10,12,13,18 3.81% [6] 42 c.5843CA>TG/c.5843C>T p.Pro1948Leu 11 4.8% [14] 42 c.5844A>G p.Pro1948Pro 1,2,5,8,10,12,13 33.3% [14] 44 c.6069C>T p.Ile2023Ile 9,12,14,19 19.1% [6] 45 c.6249C>T p.Ile2083Ile 9,12,14,19 19.1% [5] 46 c.6285T>C p.Asp2095Asp 1,2,8,9,10,12,14,19 38.1% [14] IVS48 c.6769+21C>T SPLICE 1,10 9.5% [6] 49 c.6764G>T p.Ser2255Ile 1,9,14,19 19.1% [5] Several polymorphisms in exons and introns (IVS) throughout the entire ABCA4 gene were found in our study population. Login to comment

PMID: 17296903 [PubMed] Downs K et al: "Molecular testing for hereditary retinal disease as part of clinical care."

No. Sentence Comment

116 5603A → T The sequence change alters the amino acid at position 1868, from asparagine to isoleucine. 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: 14609928 [PubMed] Margalit E et al: "Stargardt disease in a patient with retinoblastoma."

No. Sentence Comment

53 Inthispatient,thechipdetected 5sequencevariants:H423R,P1401P, IVS33+48CϾT,N1868I,andL1894L, allofwhichareconsiderednonpatho- genic polymorphisms. Login to comment
52 Inthispatient,thechipdetected 5sequencevariants:H423R,P1401P, IVS33+48Cb0e;T,N1868I,andL1894L, allofwhichareconsiderednonpatho- genic polymorphisms. Login to comment

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

No. Sentence Comment

88 Several common polymorphisms were also included, mainly from the coding region (R212H, H423R, R943Q, N1868I, P1948L, S2255I). Login to comment

PMID: 12824224 [PubMed] Schmidt S et al: "Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy."

No. Sentence Comment

123 Polymorphisms and Rare Sequence Variants in Exons of the ABCA4 Gene Exon Nucleotide Change Effect Allele Frequency* P† P§ Referenceሻ Independent ARM (n ‫؍‬ 140) All ARM (n ‫؍‬ 330) Control Subjects (n ‫؍‬ 118) 6 589G3C Asp197Asn 0.000 0.000 0.009 0.46 0.12 - 6 635G3A Arg212His 0.030 0.026 0.000 0.13 0.11 W, R 10 1268A3G His423Arg 0.394 0.371 0.427 0.62‡ 0.34 W, R 10 1269C3T His423His(syn) 0.033 0.039 0.031 1.0 0.74 W 18 2701A3G Thr901Ala 0.000 0.003 0.000 NA 0.58 W, R 23 3495C3T Asn1165Asn(syn) 0.000 0.003 0.000 NA 0.75 - 30 4469G3A Cys1490Tyr 0.007 0.003 0.000 1.0 0.59 W 37 5206T3C Ser1736Pro 0.009 0.008 0.000 1.0 0.44 W 40 5603T3A Asn1868Ile 0.100 0.102 0.054 0.29 0.18 W 40 5682G3C Leu1894Leu(syn) 0.293 0.272 0.298 1.0 0.64 W 41 5814A3G Leu1938Leu(syn) 0.160 0.169 0.218 0.33 0.38 W 42 5843C3T Pro1948Leu 0.052 0.038 0.054 1.0 0.50 W 42 5844A3G Pro1948Pro(syn) 0.199 0.192 0.205 1.0 0.77 W 44 6069C3T Ile2023Ile(syn) 0.040 0.050 0.044 1.0 0.82 W 44 6079C3T Leu2027Phe 0.000 0.000 0.009 0.48 0.13 W * Actual n (number of chromosomes) varies, as frequencies were calculated relative to nonmissing data only. Login to comment

PMID: 12153800 [PubMed] Frisch IB et al: "Kjellin's syndrome: fundus autofluorescence, angiographic, and electrophysiologic findings."

No. Sentence Comment

69 intragenic polymorphisms 5603AϾT (N1868I), 5682GϾC (L1894I), and IVS28 ϩ 43GϾA (Fig 7). Login to comment
71 We therefore decided to use polymerase chain reaction amplification and directly sequence all coding exons and flanking intronic sequences of the patient`s ABCA4 gene by using primer sequences and polymerase chain reaction conditions as described previously in Rivera et al.12 Besides the N1868I and IVS28 ϩ 43GϾA polymorphisms, the patient was also heterozygous for DNA variants IVS6-32TϾC, 3331AϾC (R1111R), 5814AϾG (L1938L), IVS43-16GϾA, and 6285TϾC (D2095D). Login to comment

PMID: 11973624 [PubMed] Maugeri A et al: "The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe."

No. Sentence Comment

41 (N1868I) and 5682G4C (L1894L), invariably present in all 16 disease chromosomes, whether from the Netherlands, Germany or Sweden (Figure 2). Login to comment
89 Interestingly, functional studies23 showed a small but reproducible decrease in ATPase activity, relative to wild type, for the N1868I (5603A4T) protein. Login to comment
88 Interestingly, functional studies23 showed a small but reproducible decrease in ATPase activity, relative to wild type, for the N1868I (5603A4T) protein. Login to comment

PMID: 11687513 [PubMed] Shroyer NF et al: "Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa."

No. Sentence Comment

102 ABCR Alterations in Patients with Stargardt Disease and Retinitis Pigmentosa Exon Nucleotide Amino Acid AR682-03 AR682-04 3 302ϩ26 A/A A/G 10 1268G 3 A H423R A/A A/G 1356ϩ11delG 6G/6G 6G/7G 15 2300T 3 A V767D T/T T/A 17 2588G 3 C G863A G/C G/G 19 2828G 3 A R943Q G/A G/G 24 3523-30 A/T A/T 28 4203C 3 A P1401P C/A C/C 4222T 3 C W1408R C/T C/T 33 4667ϩ48 C/T T/T 35 4918C 3 T R1640W C/T C/T 40 5585-70 C/T T/T 5603A 3 T N1868I A/T A/A 5682G 3 C L1894L G/C G/G Mutations are indicated in bold. Login to comment
101 ABCR Alterations in Patients with Stargardt Disease and Retinitis Pigmentosa Exon Nucleotide Amino Acid AR682-03 AR682-04 3 302af9;26 A/A A/G 10 1268G 3 A H423R A/A A/G 1356af9;11delG 6G/6G 6G/7G 15 2300T 3 A V767D T/T T/A 17 2588G 3 C G863A G/C G/G 19 2828G 3 A R943Q G/A G/G 24 3523-30 A/T A/T 28 4203C 3 A P1401P C/A C/C 4222T 3 C W1408R C/T C/T 33 4667af9;48 C/T T/T 35 4918C 3 T R1640W C/T C/T 40 5585-70 C/T T/T 5603A 3 T N1868I A/T A/A 5682G 3 C L1894L G/C G/G Mutations are indicated in bold. Login to comment

PMID: 11594993 [PubMed] Eksandh L et al: "Different clinical expressions in two families with Stargardt's macular dystrophy (STGD1)."

No. Sentence Comment

96 Of these, the two in exon 40 (5603A»T causing the substitution N1868I and the sense mutation 5682G»C in the codon for Leu1894) could be excluded as disease-associated since they were found in both alleles of the gene from the asymptomatic mother in one of the families. Login to comment
113 Ex 40 5603A-ϾT N1868I A/A A/A A/A A/A A/T A/T A/A T/T Asympt. mother homozygous. 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

37 DNA samples (n=22) carrying previously identified mutations in the ABCR gene were employed as controls for evaluating the efficacy of the DG-DGGE approach in detecting sequence variations R572Q (Lewis et al. 1999), Y639X (Lewis et al. 1999), G863A (Lewis et al. 1999; Maugeri et al. 1999), A1038V (Rozet et al. 1998), T1019M (Rozet et al. 1998), 3211insGT (Lewis et al. 1999), P1380L (Lewis et al. 1999), H1406Y (Lewis et al. 1999), 4947delC (Lewis et al. 1999), H1838Y (Lewis et al. 1999), 5714+5G→A (Cremers et al. 1998), N1868I (De La Paz et al. 1999), L1938L (Rivera et al. 2000), G1961E (Allikmets et al. 1997a, 1997b), L1970F (Lewis et al. 1999), L2027F (Nasonkin et al. 1998), V2050L (Lewis et al. 1999), E2131K (Lewis et al. 1999), R2139W (Lewis et al. 1999), 6709insG (Lewis et al. 1999), D2177N (Allikmets et al. 1997a, 1997b), 2181del12 (Lewis et al. 1999). 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

65 Four missense changes, Arg212His, His423Arg, Arg943Gln, and Pro1948Leu, were found at approximately equal frequency among patients and normal control subjects (P Ͼ 0.05 by Fisher`s two-tailed analysis) and were thus categorized as nonpathogenic polymorphisms. Login to comment
66 Asn1868Ile was less frequent in patients with Stargardt disease than in control subjects (42/252 patient alleles and 50/170 control alleles; P ϭ 0.002 by Fisher`s two-tailed analysis) and was therefore considered nonpathogenic. Login to comment

PMID: 11384574 [PubMed] Shroyer NF et al: "Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease?"

No. Sentence Comment

60 ABCR Coding Alterations in Patients With Chloroquine and Hydroxychloroquine Retinopathy Exon Nucleotide* Amino Acid* Patient Number 1 2 3 4 5 6 7 8 6 635 Arg212His G/G G/G G/G G/G G/G G/G A/G G/G 10 1268 His423Arg A/A A/A A/A G/G A/A A/A A/A A/A 1269 His423His C/C C/C C/C C/C C/C C/T C/T C/C 20 2964 Leu988Leu C/C C/C C/C C/C C/C C/C C/T C/C 23 3385 Arg1129Cys† C/C C/C C/T† C/C C/C C/C C/C C/C 24 3602 Leu1201Arg† T/T T/T T/T T/T T/T T/T T/G† T/T 28 4203 Pro1401Pro C/C C/C C/C C/A C/A C/C C/C C/C 40 5603 Asn1868Ile A/A A/A A/A A/T A/T A/A A/A A/A 5682 Leu1894Leu G/G G/C G/C G/C G/C G/G C/C G/G 41 5814 Leu1938Leu A/A A/G A/G A/A A/A A/A G/G A/A 42 5844 Pro1948Pro A/A A/G A/G A/A A/A A/A G/G A/A 44 6069 Ile2023Ile C/C C/C C/C C/C C/C C/T C/C C/T 45 6249 Ile2083Ile C/C C/C C/C C/C C/C C/T C/C C/T 46 6285 Asp2095Asp T/T T/T T/T T/T T/T T/T C/C T/C 6320 Arg2107His† G/G G/G G/G G/G G/G G/G A/A† G/G 49 6764 Ser2255Ile G/G G/G G/G G/G G/G G/G G/T G/T *Standard amino acid and nucleotide abbreviations are used. Login to comment
63 Subject 4 is also heterozygous for the transversion 5603A3T, which by conceptual translation results in the substitution of Ile for Asn (Asn1868Ile). Login to comment
64 Subject 5 is heterozygous for the substitution Asn1868Ile, and subject 8 is heterozygous for the substitution Ser2255Ile. 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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109 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 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
155 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
162 The Asn1868Ile variant was found in 71 patients with Stargardt disease and was homozygous in 8 of these. Login to comment
168 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 They also occurred together in one patient with AMD who was homozygous for Ser2255Ile and heterozygous for Asn1868Ile. Login to comment
171 For instance, Asn1868Ile was always associated with CTC at codon 1894 (Leu3Leu). Login to comment
173 Furthermore, the missense changes Gly863Ala and Arg943Gln were commonly found together. 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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110 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
131 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
156 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
164 The Asn1868Ile variant was found in 71 patients with Stargardt disease and was homozygous in 8 of these. Login to comment
170 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

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)."

No. Sentence Comment

106 351 Table 2 Novel and previously reported polymorphic sites identified in the ABCR gene in late-onset STGD subjects and controls (bold novel polymorphic sites) Exon Nucleotide alteration Predicted AA change STGD1 chromosomes Control chromosomes P value Reference 6 635 GÆA R212H 1/50 Simonelli et al. (2000) 7 IVS6-32 TÆC 4/48 N. F. Shroyer et al. (in preparation) 10 IVS9-14CÆÆÆÆT 22/50 (44%) 18/166 (10.8%) P<0.001 Present study 10 1268AÆG H423R 10/50 (20%) 46/170 (27%) P<0.4 Rivera et al. (2000) 10 1269CÆT H423H 4/50 (8%) 7/170 (4%) P<0.2 Rivera et al. (2000) 10 IVS10+11delG 16/50 (32%) 57/170 (33.5%) P>0.5 Papaioannou et al. (2000) 19 2828 GÆA R943Q 4/50 Allikmets et al. (1997b) 28 4203 CÆA P1401P 7/50 Maugeri et al. (1999) 33 IVS33+48TÆÆÆÆC 22/50 (44%) 48/114 (42%) P<0.5 Present study 39 IVS38-10CÆT 1/48 Maugeri et al. (1999) 40 5603AÆT N1868I 8/48 Stone et al. (1998) 41 5814AÆG L1938L 3/50 N. F. Shroyer et al. (in preparation) 42 IVS41-44CÆA 3/48 N. F. Shroyer et al. (in preparation) 42 IVS41-11GÆA 3/48 Maugeri et al. (1999) 42 5844AÆG P1948P 2/48 Maugeri et al. (1999) 44 IVS43-16GÆA 1/48 N. F. Shroyer et al. (in preparation) 44 6069CÆT I2023I 4/50 Allikmets et al. (1997b) 45 6249CÆT I2083I 4/50 Maugeri et al. (1999) 45 IVS45+7GÆA 5/50 (10%) 9/160 (5.6%) P>0.1 Papaioannou et al. (2000) 49 IVS48-3TÆC 3/50 (6%) 10/170 (5.9%) P>0.9 Maugeri et al. (1999) 49 6764GÆT S2255I 3/50 Allikmets et al. (1997b) 49 IVS49+27GÆC 2/48 Papaioannou et al. (2000) All missense mutations in late-onset STGD1 occur outside known functional regions of ABCR The positions of late-onset associated ABCR missense mutations were placed on the predicted ABCR structure that includes four regions of known function (transmembrane and ATP-binding domains in each of two symmetric halves of the protein). 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

79 Also considered pathological were missense mutations causing nonconservative amino acid changes-for example, A60T and A60E (table 2)-with the exception of those that were found at similar frequencies in the three study groups-for example, R152Q, N1868I, and V1921M (tables 3 and 4). Login to comment
83 Table 4 Polymorphisms in the ABCA4 Gene EXON AND NUCLEOTIDE CHANGE EFFECT NO. OF ALLELES REFERENCE(S) STGD (n p 288) AMD (n p 400) Control (n p 440) 6: 635GrA R212H 8 8 32 This study 7: IVS6-32TrC Unknown 53 115 130 This study 10: 1267ArG H423R 52 79 101 This study 1268CrT H423H 11 17 17 This study 14: IVS14ϩ50TrCa Unknown 22 18 9 This study 19: 2828GrAa R943Q 23 14 10 Allikmets et al. (1997a, 1997b), Maugeri et al. (1999), Papaioannou et al. (2000) 28: 4203CrA P1401P 29 13 20 Maugeri et al. (1999) 33: IVS32-38CrT Unknown 1 4 12 This study 34: IVS33-16delGT Unknown 24 8 12 This study 40: 5603ArT N1868I 37 40 46 Maugeri et al. (1999) 5682GrC L1894L 73 52 91 Maugeri et al. (1999), Papaioannou et al. (2000) 41: 5814ArG L1938L 50 68 70 This study 42: IVS41-11GrA Unknown 46 56 55 Maugeri et al. (1999) 5844ArG P1948P 40 40 39 Maugeri et al. (1999), Papaioannou et al. (2000) 5843CArTG P1948L 5 14 13 Maugeri et al. (1999) 44: IVS43-16GrA Unknown 46 48 55 Papaioannou et al. (2000) 45: IVS45ϩ7GrA Unknown 10 15 11 Papaioannou et al. (2000) 6249CrT I2083I 13 17 27 Allikmets et al. (1997a), Maugeri et al. (1999) 46: 6285TrC D2095D 38 36 33 Maugeri et al. (1999) a 2828GrA and IVS14ϩ50TrC occur on the same haplotype together with 2588GrC. Login to comment
101 Nineteen different alterations were present in 11% of the control alleles and were classified as polymorphisms (table 4); these include five nonconservative amino acid substitutions (R212H, H423R, R943Q, N1868I, and P1948L). Login to comment

PMID: 10442900 [PubMed] De La Paz MA et al: "Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration."

No. Sentence Comment

95 One polymorphism (N1868I) occurred in both the randomly selected population group and affected subjects and failed to segregate with the disease phenotype in the families. Login to comment
131 of Controls (%) P862L 2682 C 3 T 2683 C 3 T 3/112 (3.6) 3/53 (3.8) 0/56 (0) T901A 2782 A 3 G 2/112 (1.8) 0/53 (0) 1/56 (1.8) N1868I 5684 A 3 T 3/112 (2.7) 4/53 (7.5) 4/56 (7.1) L1948P* 5924 T 3 C 112/112 (100) 53/53 (100) 56/56 (100) L1948P* 5924 T 3 C 5925 G 3 A 110/112 (98) 51/53 (96) 54/56 (96) I2023I 6150 C 3 T 9/112 (8) 5/53 (9.4) 3/56 (5.4) L2026L 6160 C 3 T 0/112 (0) 0/53 (0) 0/56 (0) I2083I 6330 C 3 T 9/112 (8) 4/53 (7.5) 5/56 (8.9) * Variants identified in probands only. Login to comment

PMID: 9843201 [PubMed] Stone EM et al: "Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration."

No. Sentence Comment

23 The 3 common variants (Asn1868Ile, Arg943Gln and Ser2255Ile) were all present in more than 4% of all 3 groups. Login to comment
69 Three non-conservative variants (Asn1868Ile, Arg943Gln and Ser2255Ile) were very common (>4%) in all three groups. Login to comment
78 Neither of these changes was detected by Dean et al. nor did they detect a very common (15.8% overall in our study) non-conservative sequence change in exon 40 (Asn1868Ile). Login to comment

PMID: 23419329 [PubMed] Chacon-Camacho OF et al: "ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation."

No. Sentence Comment

82 These mutations were p.R24W, p.G818E, p.P1380L, p.V1682_V1686del, p.R1705Q, p.A1773V, p.I1775N, p.Y1779H, and p.N1868I. Login to comment
100 Allele 1 Allele 2 Genotype Exon Nucleotide change Polypeptide change Exon Nucleotide change Polypeptide change Familial case # 1 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 2 e NI e e NI e e 3 6 c.634C>T p.R212C (D) 38 c.5318C>T p.A1773V (D) Compound heterozygous 4 23 c.3386G>T p.R1129L (D) 28 c.4139C>T p.P1380L (D) Compound heterozygous 5 e NI e e NI e e 6 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 7 e NI e e NI e e 8 16 c.2453G>A p.G818E (D) 28 c.4249_4251 delTTC p.F1417del (D; N) Compound heterozygous 9 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous Sporadic case # 1 8 c.868C>T p.R290W (D) e IVS8&#fe;1G>A Splicing (D; N) Compound heterozygous 2 38 c.5318C>T p.A1773V (D) - NI - Heterozygous 3 20 c.3041T>G p.L1014R (D) 1; 49 c.52C>T; c.6764G>T p.R18W (D); p.S2255I (B) Compound heterozygous 4 13; 19 c.1804C>T; c.2828G>A p.R602W (D); p.R943Q (U) 16 c.2453G>A p.G818E (D) Compound heterozygous 5 38 c.5324T>A p. I1775N (D; N) 38 c.5324T>A p.I1775N (D; N) Homozygous 6 e NI e e NI e e 7 49 c.6764G>T p.S2255I (B) 49 c.6764 G>T p.S2255I (B) Homozygous 8 19; 40 c.2828 G>A; c.5503A>T p.R943Q (U); p.N1868I (U) 3 c.265G>T p.E89* (D; N) Compound heterozygous 9 38 c.5335T>C p.Y1779H (D;N) 38 c.5335T>C p.Y1779H (D;N) Homozygous 10 16 c.2453G>A p.G818E (D) 16 c.2453G>A p.G818E (D) Homozygous 11 6 c.723A>T p.E241D (D;N) 36 c.5114G>A p.R1705Q (D) Compound heterozygous 12 2 c.71G>A (D) p.R24H e NI e Heterozygous 13 30 c.4537_4538insC p.Q1513Pfs*41 (D; N) e NI e Heterozygous 14 32 c.4667G>C p.R1556T (D; N) 32 c.4667G>C p.R1556T (D; N) Homozygous 15 45 c.6221G>T p.G2074V (D; N) 16 c.2453G>A p.G818E (D) Compound heterozygous 16 16; 41 c.2453G>A; c.5824G>C p. G818E (D); p. E1942Q (B;N) 46 c.6384A>G p.H2128R (D) Compound heterozygous 17 16 c.2453G>A p. G818E (D) e NI e Heterozygous 18 32 c.4653G>A p. W1551* (D; N) e NI e Heterozygous 19 23 c.3386G>T p. R1129L (D) e NI e Heterozygous 20 36 c.5045_5059del GTTGCCATCTGCGTG p.V1682_ V1686del (D; N) 29; 49 c.4328G>A; c.6764G>T p.R1443H (D); p.S2255I (B) Compound heterozygous 21 19 c.2894A>G p.N965S (D) 19 c.2894A>G p.N965S (D) Homozygous 22 e NI e e NI e e STGD accounts for approximately 7% of all retinal dystrophies; it is one of the most common genetic forms of juvenile or early adult onset macular degeneration. Login to comment
119 ABCA4 Exon # Nucleotide change Predicted protein effect Number of alleles Population genotypic frequency in EVS Population allelic frequency in EVS (%) 1 c.52C>T p.R18W 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 2 c.71G>A p.R24H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 3 c.265G>T p.E89* (N) 1 NR NR 6 c.634C>T p.R212C 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 6 c.723A>T p.E241D (N) 1 NR NR 8 c.868C>T p.R290W 1 NR NR IVS8 IVS8 &#fe; 1G>A Splicing mutation (N) 1 NR NR 13 c.1804C>T p.R602W 1 NR NR 16 c.2453G>A p.G818E 7 NR NR 19 c.2828G>A p.R943Q 2 AA &#bc; 8/AG &#bc; 400/GG &#bc; 6095 A &#bc; 3.199/G &#bc; 96.801 19 c.2894A>G p.N965S 2 GG &#bc; 0/GA &#bc; 1/AA &#bc; 6502 G &#bc; 0.008/A &#bc; 99.992 20 c.3041T>G p.L1014R 1 NR NR 23 c.3386G>T p.R1129L 2 NR NR 28 c.4139C>T p.P1380L 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 28 c.4249_4251del TTC p.F1417del (N) 1 NR NR 29 c.4328G>A p.R1443H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 30 c.4537_4538insC p.Q1513Pfs*41 (N) 1 NR NR 32 c.4653G>A p.W1551* (N) 1 NR NR 32 c.4667G>C p.R1556T (N) 2 NR NR 36 c.5044_5058del GTTGCCATCTGCGTG p.V1682_V1686del (N) 1 NR NR 36 c.5114G>A p.R1705Q 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 38 c.5318C>T p.A1773V 8 NR NR 38 c.5324T>A p.I1775N (N) 2 NR NR 38 c.5335T>C p.Y1779H (N) 2 NR NR 40 c.5503A>T p.N1868I 1 TT &#bc; 16/TA &#bc; 589/AA &#bc; 5898 T &#bc; 4.775/A &#bc; 95.225 41 c.5824G>C p.E1942Q (N) 1 NR NR 45 c.6221G>T p.G2074V (N) 1 NR NR 46 c.6384A>G p.H2128R 1 NR NR 49 c.6764G>T p.S2255I 4 TT &#bc; 516/TG &#bc; 1473/GG &#bc; 4514 T &#bc; 19.26/G &#bc; 80.74 gold standard for ABCA4 mutational screening. Login to comment
126 Interestingly, five out of 46 mutant alleles (11%) were complex alleles (p.R18W &#fe; p.S2255I; p.R602W &#fe; p.R943W; p.R943W &#fe; p.N1868I; p.G818E &#fe; p.E1942Q; and p.R1443H &#fe; p.S2255I), a frequency that is in agreement with previous reports (Lewis et al., 1999; Shroyer et al., 2001; Zernant et al., 2011). Login to comment
138 It is important to make note that three of the variants identified in this work, p.R943Q, p.N1868I, and p.S2255I have an allele frequency in the NHLBI Exome Sequencing Project of 3.2%, 4.8%, and 19% respectively, and thus they are most probably non-pathogenic variants. Login to comment
139 However, with the exception of sporadic case #7 who was homozygous for p.S2255I (sporadic case #7 in Table 1), all remaining 4 patients carrying one of such mutations also carry two additional deleterious ABCA4 mutations (sporadic cases #4, #3, and #20 in Table 1) or a null allele (p.E89*) combined with p.R943Q and p.N1868I (sporadic case #8). Login to comment
141 Moreover, in vitro studies have shown that the ATPase activity of the p.R943Q protein function was reduced about 40% with respect to wild type ABCA4 (Su&#e1;rez et al., 2002) and carriers of p.N1868I variant exhibit a more than twofold risk of developing STGD than those carrying the normal homozygous variant (Aguirre-Lamban et al., 2011). Login to comment
142 Thus, despite its prevalence in general population, the role of the p.R943Q and N1868I ABCA4 mutations in STGD disease is controversial. Login to comment

PMID: 23443024 [PubMed] Jonsson F et al: "Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family."

No. Sentence Comment

89 Of the exonic variants, only p.N1868I and p.H423R were non-synonymous. Login to comment
90 Bioinformatics analysis predicted p.N1868I to be possibly damaging for protein function, whereas p.H423R was predicted to be benign. Login to comment
91 Segregation analysis was done for three ABCA4 sequence variants, including p.N1868I, c.4773&#fe; 3A4G and c.5461-10T4C. Login to comment
92 The variant p.N1868I was found in homozygous form in STGD1 patient VI:10, and in heterozygous form in STGD1 patient V:4 and non-affected individuals V:6, V:7 and VI:8 (Figure 1a). Login to comment
93 To determine if p.N1868I was a common variant in our population, we tested 115 control individuals from a matched geographic region and detected 16 heterozygous carriers. Login to comment
117 None of our healthy controls carried the c.5461-10T4C mutation, in line with previous observations of different population carrier frequencies.35 Interestingly, our STGD1 patients carried the sequence variant ABCA4 p.N1868I that was predicted to be possibly damaging, as well as acting as a risk-increasing factor in AMD.36 In our study, this variant was detected in almost 14% of the healthy controls, which is higher compared with the maximal frequency of 7.5% reported in a Finnish population in the 1000 Genomes project.36 It is worth mentioning that ABCA4 c.2588G4C (p.G863A), the most frequent autosomal recessive mutation in the European population, is disease causative only in combination with a severe ABCA4 mutation,32 and does not result in a STGD1 phenotype when present bi-allelic or in combination with a mild ABCA4 mutation. Login to comment
119 The same phenomena can also be applied to p.N1868I. Login to comment
124 This result was not unexpected, as ABCA4 mRNA is expressed exclusively in retina.38 Table 3 ABCA4 sequence variants in STGD1 patient Position Nucleotide change Amino-acid change RefSNP SIFT PolyPhen Splice site effect MAF (minor allele frequency) Exon 10 c.1268A4G p.H423R rs3112831 Tolerated Benign - C &#bc; 0.246/538b Exon 28 c.4203C4A p.P1401P rs1801666 -a - - A &#bc; 0.005/12b Exon 40 c.5603A4T p.N1868I rs1801466 Possibly damaging Possibly damaging - A &#bc; 0.029/63b A &#bc; 0.139/115c Exon 40 c.5682G4C p.L1894L rs1801574 - - - G &#bc; 0.219/478b - Intron 3 c.302 &#fe; 26A4G - rs2297634 - - None T &#bc; 0.470/1026b Intron 7 c.769-32T4C - rs526016 - - None G &#bc; 0.228/497b Intron 9 c.1240-14C4T - rs4147830 - - None G &#bc; 0.477/1041b Intron 13 c.1761-54G4A - rs4147833 - - Cryptic site T &#bc; 0.377/824b Intron 26 c.3863-73_3863-64delA - rs4147892 - - None NAb Intron 33 c.4773 &#fe; 3A4G New variant - - Weak NAb G &#bc; 0.009/113c Intron 38 c.5461-10T4C rs1800728 - - Weak NAb C &#bc; 0.000/116c Intron 38 c.5461-51delA rs4147899 - - none &#bc; 0.215/469b aNot predictable. 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