ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1316T>G (p.Phe439Cys)

gnomAD frequency: 0.00006  dbSNP: rs141585847
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199551 SCV000252527 uncertain significance not provided 2024-12-11 criteria provided, single submitter clinical testing Reported as heterozygous in an individual with suspected monogenic diabetes (PMID: 33242514); Reported in individuals undergoing genetic testing for indications unrelated to known WFS1-related disorders (PMID: 31589614, 32771712, 31862442); 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: 34426522, 31589614, 26435059, 31862442, 32771712, 36208030, 36147510, 33242514, 24890733)
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375053 SCV001571767 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Moderate, PP3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV000199551 SCV002283056 uncertain significance not provided 2023-12-14 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 439 of the WFS1 protein (p.Phe439Cys). This variant is present in population databases (rs141585847, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 24890733). ClinVar contains an entry for this variant (Variation ID: 215388). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. 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 RCV005025322 SCV005660233 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-04-13 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004530180 SCV004716134 uncertain significance WFS1-related disorder 2023-10-26 no assertion criteria provided clinical testing The WFS1 c.1316T>G variant is predicted to result in the amino acid substitution p.Phe439Cys. This variant was reported in the heterozygous state in an individual with early onset Wolfram syndrome (Chaussenot et al. 2015. PubMed ID: 24890733). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6302838-T-G). 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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