Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000726781 | SCV000702983 | likely pathogenic | not provided | 2016-11-02 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001267554 | SCV001445735 | likely pathogenic | Inborn genetic diseases | 2019-10-04 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000726781 | SCV002307708 | pathogenic | not provided | 2023-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 829 of the WFS1 protein (p.Leu829Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant deafness or clinical features of autosomal recessive Wolfram syndrome (PMID: 11709537, 17492394, 31363008). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4521). 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. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155015 | SCV003845070 | pathogenic | Wolfram syndrome 1 | 2023-02-03 | criteria provided, single submitter | clinical testing | Variant summary: WFS1 c.2486T>C (p.Leu829Pro) results in a non-conservative amino acid change located in the Wolframin, OB-fold domain (IPR045461) 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 248518 control chromosomes (gnomAD). c.2486T>C has been reported in the literature in the heterozygous state in multiple individuals affected Autosomal Dominant Nonsyndromic Sensorineural Heaing Loss (e.g. Bespalova_2001, Sloan-Heggen_2016, Lusk_2020) and in the compound heterozygous state in at least two individuals with Wolfram Syndrome (Lusk_2020). 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. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gene |
RCV000726781 | SCV003923376 | pathogenic | not provided | 2023-05-01 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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: 12650912, 20738327, 12955714, 12707188, 12707187, 18776598, 17492394, 19877185, 12181639, 31363008, 11709537, 37121227, 36225977, Zhao2023[paper]) |
| OMIM | RCV000004779 | SCV000024955 | pathogenic | Autosomal dominant nonsyndromic hearing loss 6 | 2024-03-06 | no assertion criteria provided | literature only |