ClinVar Genomic variation as it relates to human health

Variant summary: ABCA4 c.2827C>T (p.Arg943Trp) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251418 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Stargardt Disease (8e-05 vs 0.0014), allowing no conclusion about variant significance. c.2827C>T has been reported in the literature in multiple compound heterozygous individuals affected with Stargardt Disease (e.g., Briggs_2001, Weisschuh_2020, Sun_2021, Huang_2022) and retinitis pigmentosa (e.g., Sung_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11527935, 26992781, 9973280, 33301772, 33261146, 32531858, 11379881, 36209838). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (pathogenic, n = 2; uncertain significance, n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The ABCA4 c.2827C>T variant is predicted to result in the amino acid substitution p.Arg943Trp. This variant has been reported along with a second ABCA4 variant in multiple individuals with autosomal recessive Stargardt disease (Lewis et al. 1999. PubMed ID: 9973280; Briggs et al. 2001. PubMed ID: 11527935; Patient31, Table S2 in Sung et al. 2020. PubMed ID: 33261146; Table S1 in Weisschuh et al. 2020. PubMed ID: 32531858). Of note, an alternate substitution of this same amino acid residue, p.Arg943Gln, is reported with a very high minor allele frequency (4.2% of alleles in individuals of South Asian descent in gnomAD: http://gnomad.broadinstitute.org/variant/1-94512565-C-T), and therefore we interpret it as benign. This p.Arg943Trp variant, on the other hand, is reported in 0.054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94512566-G-A). Given all the evidence, we interpret c.2827C>T (p.Arg943Trp) as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 943 of the ABCA4 protein (p.Arg943Trp). This variant is present in population databases (rs61749446, gnomAD 0.05%). This missense change has been observed in individual(s) with retinitis pigmentosa and/or Stargardt disease (PMID: 9973280, 11379881, 11527935, 31884623, 33261146, 33301772). 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: 99162). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

ABCA4: PM3:Very Strong, PM1, PM2