ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2266C>T (p.Arg756Cys)

gnomAD frequency: 0.00022  dbSNP: rs138127684
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002265152 SCV002546752 uncertain significance not provided 2024-05-07 criteria provided, single submitter clinical testing 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: 11709537, 23595122)
Labcorp Genetics (formerly Invitae), Labcorp RCV002265152 SCV003242847 uncertain significance not provided 2023-11-15 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 756 of the WFS1 protein (p.Arg756Cys). This variant is present in population databases (rs138127684, gnomAD 0.1%). This missense change has been observed in individual(s) with deafness (PMID: 23595122). ClinVar contains an entry for this variant (Variation ID: 1695517). 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 expected to disrupt WFS1 protein function with a positive 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.
New York Genome Center RCV003228060 SCV003925342 uncertain significance Type 2 diabetes mellitus 2022-04-08 criteria provided, single submitter clinical testing The c.2266C>T (p.Arg756Cys) missense variant identified in WFS1 has been reported in individuals affected with sensorineural hearing impairment [PMID:11709537, 23595122]. The variant has a 0.00019704 allele frequency in the gnomAD(v3) database (30 out of 152258 heterozygous alleles, no homozygotes), and 0.000060448 allele frequency in the TOPMed Freeze 8 database (16 out of 132,345 heterozygous alleles, no homozygotes). This variant replaces highly conserved arginine residue [Arg756] and is predicted deleterious by multiple in silico tools (CADD score = 33, REVEL score = 0.772). Based on the available evidence, the c.2266C>T (p.Arg756Cys) missense variant identified in the WFS1 gene is reported as a Variant of Uncertain Significance.

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