Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001953886 | SCV002240659 | pathogenic | not provided | 2024-03-14 | 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 1368 of the ABCA4 protein (p.Arg1368Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 22229821). ClinVar contains an entry for this variant (Variation ID: 1457682). 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%. This variant disrupts the p.Arg1368 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003331250 | SCV004037612 | pathogenic | Stargardt disease | 2023-08-28 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.4102C>T (p.Arg1368Cys) results in a non-conservative amino acid change in 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 4e-06 in 249432 control chromosomes. c.4102C>T has been reported in the literature along with at-least five different apparently pathogenic variants in multiple individuals affected with Stargardt Disease (STGD), inherited retinal dystrophies or retinal dystrophy (examples, Duno_2012, Bertelsen_2014, Hanany_2020, Jiang_2015, Saleh_2021), and has been reported to be enriched in 3928 likely Caucasian STGD1 patients compared to the non-Finnish ExAC population (Cornelis_2017). These data indicate that the variant is very 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: 24713488, 22229821, 31964843, 26780318, 28044389, Saleh_2021 without PMID). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Institute of Human Genetics, |
RCV004816828 | SCV005070561 | likely pathogenic | Retinal dystrophy | 2020-01-01 | criteria provided, single submitter | clinical testing |