Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001806811 | SCV002051313 | likely pathogenic | Wolfram syndrome 1 | 2021-12-21 | criteria provided, single submitter | clinical testing | Variant summary: WFS1 c.397G>A (p.Ala133Thr) results in a non-conservative amino acid change located in the Wolframin, Sel1-like repeat (IPR045458) of 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 1.4e-05 in 206924 control chromosomes (gnomAD). c.397G>A has been reported in the literature in multiple compound heterozygous individuals affected with Wolfram Syndrome 1 (example: Giuliano_2005, Hansen_2005, Swift_2005). 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. No ClinVar submitters have assessed the variant since 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV001814605 | SCV002061697 | uncertain significance | not provided | 2021-11-05 | criteria provided, single submitter | clinical testing | PP3, PM2 |
| Labcorp Genetics |
RCV001814605 | SCV002240956 | pathogenic | not provided | 2023-08-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 1331467). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 15605410, 16151413). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 133 of the WFS1 protein (p.Ala133Thr). |
| Gene |
RCV001814605 | SCV004025609 | uncertain significance | not provided | 2023-08-09 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11317350, 15852062, 19292454, 20972738, 16151413, 15605410, 33980734, 22790102) |
| Fulgent Genetics, |
RCV005038334 | SCV005664675 | likely pathogenic | Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome | 2024-04-03 | criteria provided, single submitter | clinical testing |