ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1492G>A (p.Val498Ile)

gnomAD frequency: 0.00013  dbSNP: rs71524358
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001593670 SCV001816781 uncertain significance not provided 2023-02-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002476898 SCV002782659 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2022-04-15 criteria provided, single submitter clinical testing
Invitae RCV001593670 SCV003204172 uncertain significance not provided 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 498 of the WFS1 protein (p.Val498Ile). This variant is present in population databases (rs71524358, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1216007). 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.
PreventionGenetics, part of Exact Sciences RCV004536218 SCV004728194 uncertain significance WFS1-related disorder 2023-10-28 criteria provided, single submitter clinical testing The WFS1 c.1492G>A variant is predicted to result in the amino acid substitution p.Val498Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6303014-G-A). 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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