Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001230252 | SCV001402726 | pathogenic | not provided | 2023-09-29 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 967 of the ABCA4 protein (p.Ala967Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stargardt disease (PMID: 31934596; Invitae). ClinVar contains an entry for this variant (Variation ID: 957296). 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. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001230252 | SCV001996236 | uncertain significance | not provided | 2019-10-09 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31934596) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004587084 | SCV005076343 | likely pathogenic | Retinitis pigmentosa | 2024-04-12 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.2900C>T (p.Ala967Val) 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 was absent in 251278 control chromosomes. c.2900C>T has been reported in the literature as a biallelic homzygous genotype in an individual from at-least one South Indian family affected with Stargardt Disease 1 (to include Retinitis Pigmentosa) (example, Raj_2020). Another study reporting personalized genetic counseling for Stargardt disease based on variant severity lists this variant among those with a moderate/severe category stating an offspring risk of 1.7-1.9% among carrier couples (Cornelis_2022). 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: 35120629, 31934596). ClinVar contains an entry for this variant (Variation ID: 957296). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Fulgent Genetics, |
RCV005036499 | SCV005659485 | likely pathogenic | Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 | 2024-04-18 | criteria provided, single submitter | clinical testing |