Submissions for variant NM_006005.3(WFS1):c.2192T>C (p.Met731Thr)

gnomAD frequency: 0.00001  dbSNP: rs146418094

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520878	SCV000621172	uncertain significance	not provided	2017-09-26	criteria provided, single submitter	clinical testing	The M731T variant in the WFS1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M731T variant is not observed in large population cohorts (Lek et al., 2016). The M731T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret M731T as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002481734	SCV002785518	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-01-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520878	SCV003266224	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 731 of the WFS1 protein (p.Met731Thr). This variant is present in population databases (rs146418094, gnomAD 0.006%). 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: 452367). 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126795	SCV003802910	uncertain risk allele	Wolfram syndrome 1		criteria provided, single submitter	research	Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs146418094 in Wolfram's syndrome yet.