ClinVar Genomic variation as it relates to human health

The ABCA4 c.5113C>T (p.Arg1705Trp) missense variant has been reported in at least three studies in which it is found in at least two patients in a compound heterozygous state, one of whom was diagnosed with Stargardt disease before age ten and one diagnosed with a retinopathy noted to be consistent with ABCA4-related retinal disease (Ernest et al. 2009; Fujinami et al. 2013; Lambertus et al. 2015). The p.Arg1705Trp variant was absent from 100 controls and is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg1705Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

_x000D_ Criteria applied: PM3, PM2_SUP, PM5_SUP, PP3, PP4

Criteria applied: PM1,PM5,PM2_SUP,PP3,PP4, PS4_MOD

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) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1705 of the ABCA4 protein (p.Arg1705Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Stargardt disease (PMID: 25444351, 32307445; Invitae). ClinVar contains an entry for this variant (Variation ID: 632119). This variant disrupts the p.Arg1705 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17325179, 23419329, 23769331). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Criteria applied: PM2,PM3,PM5,PP3

The ABCA4 c.5113C>T variant is predicted to result in the amino acid substitution p.Arg1705Trp. This variant has been reported along with a second ABCA4 variant in individuals with ABCA4-related retinal disease (Fujinami et al. 2013. PubMed ID: 23982839; Lambertus et al. 2014. PubMed ID: 25444351; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858;Table S1, Lin et al. 2024. PubMed ID: 38219857). Alternate substitutions of this amino acid residue (p.Arg1705Leu and p.Arg1705Gln) have also been reported in individuals with ABCA4-related retinal disease (Table S1, Fujinami et al. 2018. PubMed ID: 29925512). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.