Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001063595 | SCV001228449 | pathogenic | not provided | 2023-12-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 811 of the ABCA4 protein (p.Arg811Cys). This variant is present in population databases (rs758777521, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa and/or Stargardt disease (PMID: 24428930, 34315337). 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: 857838). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235461 | SCV003934469 | uncertain significance | not specified | 2023-05-31 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.2431C>T (p.Arg811Cys) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250982 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Stargardt Disease (6.8e-05 vs 0.0014), allowing no conclusion about variant significance. c.2431C>T has been reported in the literature in the compound heterozygous state in an individual affected with Stargardt Disease and as a heterozygous genotype in an individual affected with retinitis pigmentosa (Singh_2014, Duzkale_2021). It has also been reported in the heterozygous state as part of a complex allele in an individual suspected of Stargardt Disease (Khan_2020). These data do not allow any strong conclusion about variant significance. 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: 34315337, 32307445, 24428930). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |