Submissions for variant NM_006005.3(WFS1):c.1181A>T (p.Glu394Val)

gnomAD frequency: 0.00006  dbSNP: rs146563951

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657864	SCV000779624	uncertain significance	not provided	2022-08-17	criteria provided, single submitter	clinical testing	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: 12955714, 20738327, 26435059, 33841295, 34746052, 11920861, 26934580)
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001644744	SCV001519272	likely pathogenic	Spastic ataxia	2021-07-12	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657864	SCV002255083	uncertain significance	not provided	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 394 of the WFS1 protein (p.Glu394Val). This variant is present in population databases (rs146563951, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 37108562). ClinVar contains an entry for this variant (Variation ID: 546078). 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) indicates that this missense variant is expected to disrupt WFS1 protein function with a positive 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	RCV000657864	SCV002497249	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005027770	SCV005660224	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-02-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737937	SCV005366747	uncertain significance	WFS1-related disorder	2024-07-10	no assertion criteria provided	clinical testing	The WFS1 c.1181A>T variant is predicted to result in the amino acid substitution p.Glu394Val. This variant was reported in a patient with optic neuropathy (Table S2, Charif. 2021. PubMed ID: 33841295) and was identified in a study of individuals that had completed suicide related to potential psychiatric disorders (Crawford. 2002. PubMed ID: 11920861). This variant was also reported in a patient with hereditary ataxia (Supplemental Tables, Galatolo. 2021. PubMed ID: 34445196) and an unaffected individual in a cohort of patients with hearing loss (Supplementary Data, Quaio. 2022. PubMed ID: 36147510 ). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including >200 heterozygotes in the gnomAD v4.0.0 dataset. While we suspect this variant may be benign for autosomal dominant disorders, at this time the clinical significance of this variant is uncertain in regards to autosomal recessive Wolfram syndrome due to the absence of conclusive functional and genetic evidence.