Submissions for variant NM_006005.3(WFS1):c.883G>A (p.Ala295Thr)

gnomAD frequency: 0.00001  dbSNP: rs537052067

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152669	SCV000202028	uncertain significance	not specified	2017-03-09	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala295Thr var iant in WFS1 has been previously identified by our laboratory in one Saudi indiv idual with an alternate genetic etiology for the hearing loss. There is limited control information for the WFS1 gene on the Saudi population; therefore, we can not rule out that this variant is part of the spectrum of benign variation in th is population. This variant has been identified in 1/66652 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs537052067). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. Alanine (Ala) at p osition 295 is not conserved in mammals or in evolutionarily distant species, wi th 1 mammal (Aardvark) having a threonine (Thr) at this position. Additional com putational prediction tools suggest that this variant may not impact the protein , though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ala295Thr variant is uncertai n, available data suggest that it is more likely to be benign.
Invitae	RCV001309844	SCV001499357	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 295 of the WFS1 protein (p.Ala295Thr). This variant is present in population databases (rs537052067, gnomAD 0.005%). 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: 166580). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001309844	SCV002497248	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002265628	SCV002548691	uncertain significance	Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Wolfram-like syndrome	2021-08-14	criteria provided, single submitter	clinical testing	The inherited missense variant c.883G>A, p.Ala295Thr identified in the WFS1 gene has not been reported in individuals with WFS1-related disorders. This variant has two heterozygous (0.001%) in gnomAD v3.1.1, suggesting it is not a common benign variant in the populations represented in this database. In silico tools predict conflicting evidence of pathogenicity. Based on the available evidence, the c.883G>A, p.Ala295Thr variant in the WFS1 gene is classified as a variant of uncertain significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509251	SCV002774919	uncertain significance	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 rs537052067 in Wolfram's syndrome yet.
Ambry Genetics	RCV002516066	SCV003750663	uncertain significance	Inborn genetic diseases	2023-10-25	criteria provided, single submitter	clinical testing	The c.883G>A (p.A295T) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 883, causing the alanine (A) at amino acid position 295 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001309844	SCV005079233	uncertain significance	not provided	2024-02-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Breakthrough Genomics, Breakthrough Genomics	RCV001309844	SCV005190020	uncertain significance	not provided		criteria provided, single submitter	not provided