ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1366C>T (p.Arg456Cys)

gnomAD frequency: 0.00006  dbSNP: rs144452795
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001768391 SCV002008996 uncertain significance not provided 2024-07-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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: 33841295, 35982159, 35982160, 25133958)
Labcorp Genetics (formerly Invitae), Labcorp RCV001768391 SCV002312291 uncertain significance not provided 2024-01-17 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 456 of the WFS1 protein (p.Arg456Cys). This variant is present in population databases (rs144452795, gnomAD 0.02%). This missense change has been observed in individual(s) with optic neuropathy (PMID: 33841295). ClinVar contains an entry for this variant (Variation ID: 1318767). 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.
Fulgent Genetics, Fulgent Genetics RCV002482285 SCV002786295 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2022-05-16 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004528532 SCV004108828 uncertain significance WFS1-related disorder 2023-04-28 criteria provided, single submitter clinical testing The WFS1 c.1366C>T variant is predicted to result in the amino acid substitution p.Arg456Cys. This variant has been reported in an individual with cerebellar ataxia who also harbored other variants (Fogel et al 2014. PubMed ID: 25133958). This variant has also been reported in a cohort of patients with optic neuropathy (Table 2, Charif M et al 2021. PubMed ID: 33841295). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6302888-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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