ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1052A>G (p.Tyr351Cys)

gnomAD frequency: 0.00006  dbSNP: rs181988441
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Total submissions: 6
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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 RCV000214867 SCV000272909 uncertain significance not specified 2015-08-11 criteria provided, single submitter clinical testing The p.Tyr351Cys variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome, but has been identified in 5/66738 Europe an American chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs181988441). Although this variant has been seen in th e general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that the p.Tyr351Cys variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, the clinical significance o f the p.Tyr351Cys variant is uncertain.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV001174389 SCV001337527 uncertain significance Monogenic diabetes 2018-01-09 criteria provided, single submitter research ACMG criteria: PP3 (10 predictors) =VUS
Labcorp Genetics (formerly Invitae), Labcorp RCV001853497 SCV002192306 uncertain significance not provided 2025-01-08 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 351 of the WFS1 protein (p.Tyr351Cys). This variant is present in population databases (rs181988441, gnomAD 0.009%). This missense change has been observed in individual(s) with WFS1-related conditions (PMID: 33841295, 36938085). ClinVar contains an entry for this variant (Variation ID: 229635). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt WFS1 protein function with a positive predictive value of 95%. 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 RCV002494578 SCV002794047 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-01-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001853497 SCV005410513 uncertain significance not provided 2024-01-09 criteria provided, single submitter clinical testing PP3
GeneDx RCV001853497 SCV005882198 uncertain significance not provided 2024-09-09 criteria provided, single submitter clinical testing Reported in a patient with optic neuropathy in published literature (PMID: 33841295); 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: 36938085, 26435059, 33841295)

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