ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1610G>A (p.Cys537Tyr)

gnomAD frequency: 0.00034  dbSNP: rs199910987
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200051 SCV000252530 uncertain significance not provided 2024-10-02 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign in association with a WFS1-related disorder to our knowledge; it has been published as heterozygous in patients with diabetes in a study examining genetic causes of diabetes (PMID: 33046911); 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: 31589614, 10521293, 36208030, 36147510, 33046911)
Personalized Diabetes Medicine Program, University of Maryland School of Medicine RCV001174422 SCV001337560 uncertain significance Monogenic diabetes 2018-03-27 criteria provided, single submitter research ACMG criteria: PP3 (10 predictors, REVEL=0.939), PM1 (transmembrane domain PMID:10521293)=VUS
Labcorp Genetics (formerly Invitae), Labcorp RCV000200051 SCV002198142 uncertain significance not provided 2024-12-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 537 of the WFS1 protein (p.Cys537Tyr). This variant is present in population databases (rs199910987, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 33046911). ClinVar contains an entry for this variant (Variation ID: 215390). 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.
Ambry Genetics RCV002517280 SCV003735385 uncertain significance Inborn genetic diseases 2022-08-17 criteria provided, single submitter clinical testing Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005031740 SCV005672317 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-03-08 criteria provided, single submitter clinical testing

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