Submissions for variant NM_006005.3(WFS1):c.1922C>T (p.Thr641Met)

dbSNP: rs376626985

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000732844	SCV000860836	uncertain significance	not provided	2018-04-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000732844	SCV001818210	uncertain significance	not provided	2020-11-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002477720	SCV002781336	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-05-25	criteria provided, single submitter	clinical testing
Invitae	RCV000732844	SCV003286106	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 596878). 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. This variant disrupts the p.Thr641 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with autosomal dominant nonsyndromic deafness (Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs376626985, gnomAD 0.04%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 641 of the WFS1 protein (p.Thr641Met).
PreventionGenetics, part of Exact Sciences	RCV004535859	SCV004114802	uncertain significance	WFS1-related disorder	2023-04-26	criteria provided, single submitter	clinical testing	The WFS1 c.1922C>T variant is predicted to result in the amino acid substitution p.Thr641Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.037% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6303444-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.