ClinVar Genomic variation as it relates to human health

The ABCA4 c.1531C>T (p.Arg511Cys) missense variant has been reported in four studies in which it is found in a total of six individuals with an ABCA4-related disorder. One individual with an ABCA4-related disorder of an unspecified type carried the p.Arg511Cys variant in a homozygous state (Zernant et al. 2011). Two individuals with Stargardt disease and one patient with inherited retinal dystrophy carried the p.Arg511Cys variant in a compound heterozygous state with a second variant (Jiang et al. 2016; Huang et al. 2015). One individual with Stargardt disease carried the p.Arg511Cys variant along with both a duplication and a missense variant of unclear zygosity in the ABCA4 gene (Fujinami et al. 2015). One individual with cone rod dystrophy carried the p.Arg511Cys variant with a second ABCA4 variant of unknown pathogenicity in cis and a third variant in trans (Jiang et al. 2016). The p.Arg511Cys variant was absent from 464 controls and is reported at a frequency of 0.00243 in the East Asian population of the Exome Aggregate Consortium. Based on the collective evidence, the p.Arg511Cys variant is classified as likely pathogenic for autosomal recessive ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.70; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000377402). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25356976). A different missense change at the same codon (p.Arg511His) has been reported to be associated with ABCA4 related disorder (ClinVar ID: VCV000283387). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25312043, 21911583, 26780318, 29555955, 25356976, 29925512, 31456290, 33261146, 31816670, 31964843, 32307445, 36284460, 33301772)

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 511 of the ABCA4 protein (p.Arg511Cys). This variant is present in population databases (rs752786160, gnomAD 0.2%). This missense change has been observed in individual(s) with ABCA4-related disease (PMID: 25312043, 25356976, 26780318, 30060493). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 377402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), cone-rod dystrophy 3 (MIM #6041163), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (46 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (201 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Stargardt disease and cone-rod dystrophy (ClinVar, PMID: 25356976, 25312043, 26780318, 28327576, 30060493). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PP3+PM3_VeryStrong+PP4

The ABCA4 c.1531C>T variant is predicted to result in the amino acid substitution p.Arg511Cys. This variant was reported in the homozygous state, or in the heterozygous state with a second probable causative variant, in individuals with suspected ABCA4-associated disease (supplementary data, Zernant et al. 2011. PubMed ID: 21911583; supplementary data, Huang et al. 2014. PubMed ID: 25356976; supplementary data, Khan et al. 2020. PubMed ID: 32307445; supplementary data, Lin et al. 2024. PubMed ID: 38219857; supplementary data, Chen et al. 2021. PubMed ID: 33608557; Lee et al. 2017. PubMed ID: 28327676; Mizobuchi et al. 2024. PubMed ID: 38499139). This variant was also reported in large cohorts of individuals with retinal disease, and was suggested by several authors to be a hypomorphic variant or associated with mild disease (supplementary data, Jiang et al. 2016. PubMed ID: 26780318; supplementary data, Hanany et al. 2020. PubMed ID: 31964843; supplementary data, Sung et al. 2020. PubMed ID: 33261146; supplementary data, Cornelis et al. 2022. PubMed ID: 35120629; supplementary data, Suga et al. 2022. PubMed ID: 36284460). Additionally, this variant was reported along with two or three other ABCA4 variants in individuals with suspected retinal disease (supplementary data, Birtel et al. 2018. PubMed ID: 29555955; Fujinami et al. 2018. PubMed ID: 29925512; supplementary data, Yohe et al. 2019. PubMed ID: 31816670). This variant is sometimes found in cis with c.1531C>T/p.Pro291Leu (see, for example, supplementary data, Sharon et al. 2019. PubMed ID: 31456290; Nassisi et al. 2018. PubMed ID: 30060493). This variant is reported in 0.19% of alleles in individuals of East Asian descent in gnomAD, which is somewhat high for a primary cause of disease but would be consistent with a mild/hypomorphic allele. Taken together, we classify this variant as likely pathogenic for autosomal recessive ABCA4-related disease.