Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000085737 | SCV001582798 | pathogenic | not provided | 2024-01-21 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1846 of the ABCA4 protein (p.Ile1846Thr). This variant is present in population databases (rs61750575, gnomAD 0.006%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 10090887, 23143460, 28355279; Invitae). 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: 99383). 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. |
| 3billion | RCV003152681 | SCV003842093 | likely pathogenic | Cone-rod dystrophy 3 | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic (ClinVar ID: VCV000099383). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004689603 | SCV005185705 | pathogenic | Stargardt disease | 2024-05-16 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.5537T>C (p.Ile1846Thr) 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 2e-05 in 251392 control chromosomes (gnomAD). c.5537T>C has been reported in the literature in multiple individuals affected with Stargardt Disease (e.g. Valkenburg_2019, Bax_2019). 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: 31522899, 30903310). ClinVar contains an entry for this variant (Variation ID: 99383). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Retina International | RCV000085737 | SCV000117878 | not provided | not provided | no assertion provided | not provided |