ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.527T>C (p.Val176Ala)

gnomAD frequency: 0.00001  dbSNP: rs772915458
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001787592 SCV002031054 uncertain significance not provided 2021-06-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with congenital anomalies of the kidney and urinary tract (CAKUT) in published literature (Bekheirnia et al., 2021) who had a different genetic etiology for the phenotype; Has not been previously published as pathogenic or benign in association with a WFS1-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 27535533, Bekheirnia2020)
Fulgent Genetics, Fulgent Genetics RCV002489835 SCV002782161 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001787592 SCV005831234 uncertain significance not provided 2024-07-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 176 of the WFS1 protein (p.Val176Ala). This variant is present in population databases (rs772915458, gnomAD 0.003%). This missense change has been observed in individual(s) with CAKUT syndrome (PMID: 35368817). ClinVar contains an entry for this variant (Variation ID: 1327312). 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 not expected to disrupt WFS1 protein function with a negative 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.

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