Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV001592475 | SCV001824125 | uncertain significance | not provided | 2021-03-31 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified as heterozygous in a patient with Lebers congenital amaurosis and retinitis pigmentosa who was apparently homozygous for a pathogenic PROM1 variant; this patient was also heterozygous for two other variants in WFS1, although the phase of these variants was not reported (Bryant et al., 2018); This variant is associated with the following publications: (PMID: 29343940) |
| Fulgent Genetics, |
RCV002477860 | SCV002788018 | uncertain significance | Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome | 2022-03-05 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001592475 | SCV004353419 | likely pathogenic | not provided | 2023-09-20 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 650 of the WFS1 protein (p.Tyr650Cys). This variant is present in population databases (rs765322804, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1218633). 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 WFS1 protein function. This variant disrupts the p.Tyr650 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27395765; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |