ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1633G>A (p.Val545Met)

gnomAD frequency: 0.00007  dbSNP: rs201993978
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000732082 SCV000252531 uncertain significance not provided 2022-12-02 criteria provided, single submitter clinical testing Reported as heterozygous in an individual with Wolfram syndrome; a second variant was not described (Galvez-Ruiz et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29563951)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000196092 SCV000731342 uncertain significance not specified 2018-08-30 criteria provided, single submitter clinical testing The p.Val545Met variant in WFS1 has been identified by our laboratory in 1 indiv idual with hearing loss. It has also been identified in 0.01% (18/126656) of Eur opean chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been rep orted in ClinVar (Variation ID 215391). Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Val545Met is uncertain. A CMG/AMP Criteria applied: PM2_Supporting.
Eurofins Ntd Llc (ga) RCV000732082 SCV000859987 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765783 SCV000897172 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2022-04-14 criteria provided, single submitter clinical testing
Invitae RCV000732082 SCV002232391 uncertain significance not provided 2023-11-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 545 of the WFS1 protein (p.Val545Met). This variant is present in population databases (rs201993978, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Wolfram-like syndrome (PMID: 29563951). ClinVar contains an entry for this variant (Variation ID: 215391). 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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