Submissions for variant NM_006005.3(WFS1):c.2026C>T (p.Arg676Cys)

gnomAD frequency: 0.00006  dbSNP: rs201623184

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000397077	SCV000450651	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000311200	SCV000450652	uncertain significance	WFS1-Related Spectrum Disorders	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612443	SCV000711253	uncertain significance	not specified	2016-09-08	criteria provided, single submitter	clinical testing	The p.Arg676Cys variant in WFS1 has not been previously reported in individuals with hearing loss, or Wolfram syndrome Wolfram-like disorder, but has been ident ified in 10/121020 pan-ethnic chromosomes by the Exome Aggregation Consortium (E xAC, http://exac.broadinstitute.org; dbSNP rs201623184). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summa ry, the clinical significance of the p.Arg676Cys variant is uncertain.
GeneDx	RCV001555289	SCV001776676	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing	Observed in a patient with hearing loss in published literature (PMID: 28974383); 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: 28974383)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001555289	SCV002288998	uncertain significance	not provided	2024-11-05	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 676 of the WFS1 protein (p.Arg676Cys). This variant is present in population databases (rs201623184, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 28974383). ClinVar contains an entry for this variant (Variation ID: 349321). Invitae Evidence 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 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	RCV005033885	SCV005667526	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2023-12-28	criteria provided, single submitter	clinical testing