Submissions for variant NM_006005.3(WFS1):c.535G>A (p.Ala179Thr)

gnomAD frequency: 0.00001  dbSNP: rs776685250

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214251	SCV000272923	uncertain significance	not specified	2015-08-12	criteria provided, single submitter	clinical testing	The p.Ala179Thr variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome, but has been identified in 2/8632 East As ian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs776685250). Computational prediction tools and conservation a nalyses do not provide strong support for or against an impact to the protein. I n summary, the clinical significance of the p.Ala179Thr variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV000765773	SCV000897162	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509054	SCV002773844	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 rs776685250 in Wolfram's syndrome yet.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519659	SCV003272840	uncertain significance	not provided	2024-09-03	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 179 of the WFS1 protein (p.Ala179Thr). This variant is present in population databases (rs776685250, gnomAD 0.01%). This missense change has been observed in individual(s) with deafness or diabetes (PMID: 36597107, 37277527). ClinVar contains an entry for this variant (Variation ID: 229647). 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.
CeGaT Center for Human Genetics Tuebingen	RCV002519659	SCV003916883	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002519659	SCV004167854	uncertain significance	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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
PreventionGenetics, part of Exact Sciences	RCV004737345	SCV005346603	uncertain significance	WFS1-related disorder	2024-05-14	no assertion criteria provided	clinical testing	The WFS1 c.535G>A variant is predicted to result in the amino acid substitution p.Ala179Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.