Submissions for variant NM_006005.3(WFS1):c.1969A>G (p.Met657Val)

gnomAD frequency: 0.00010  dbSNP: rs71532861

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656991	SCV000252494	uncertain significance	not provided	2018-03-20	criteria provided, single submitter	clinical testing	The M657V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M657V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The M657V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000196354	SCV000272914	uncertain significance	not specified	2016-08-30	criteria provided, single submitter	clinical testing	The p.Met657Val variant in WFS1 has been previously reported by our laboratory i n the heterozygous state in one individual with hearing loss, but has been ident ified in 4/66648 of European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs71532861). This frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Met657Val variant is unce rtain.
Illumina Laboratory Services, Illumina	RCV001153353	SCV001314639	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	RCV001153354	SCV001314640	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.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640296	SCV001519312	uncertain significance	Spastic ataxia	2021-01-04	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000196354	SCV002068552	uncertain significance	not specified	2019-01-23	criteria provided, single submitter	clinical testing
Invitae	RCV000656991	SCV002297524	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 657 of the WFS1 protein (p.Met657Val). This variant is present in population databases (rs71532861, gnomAD 0.02%). This missense change has been observed in individual(s) with spinocerebellar ataxia (PMID: 34445196). ClinVar contains an entry for this variant (Variation ID: 215365). 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 not expected to disrupt WFS1 protein function with a negative 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.
Fulgent Genetics, Fulgent Genetics	RCV002485309	SCV002786467	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-02-15	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126584	SCV003802883	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 rs71532861 in Wolfram's syndrome yet.