ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1123C>T (p.Arg375Cys)

gnomAD frequency: 0.00019  dbSNP: rs200095753
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000601338 SCV000712190 uncertain significance not specified 2016-06-04 criteria provided, single submitter clinical testing The p.Arg375Cys variant in WFS1 has not been previously reported in individuals with hearing loss. This variant has been identified in 5/10404 African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs200095753); however, its frequency is not high enough to rule out a pathog enic role. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg375Cys variant is uncertain.
Invitae RCV001857735 SCV002189650 uncertain significance not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the WFS1 protein (p.Arg375Cys). This variant is present in population databases (rs200095753, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 29563951, 31264968). ClinVar contains an entry for this variant (Variation ID: 215384). 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 with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002485310 SCV002776632 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2021-12-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV002515447 SCV003699346 uncertain significance Inborn genetic diseases 2021-08-31 criteria provided, single submitter clinical testing Unlikely to be causative of autosomal dominant Wolfram syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Computational Biology & Bioinformatics, University of California, San Diego RCV004567405 SCV005049974 uncertain significance Meniere disease 2024-06-03 no assertion criteria provided research

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