Submissions for variant NM_006005.3(WFS1):c.2053C>T (p.Arg685Cys)

gnomAD frequency: 0.00020  dbSNP: rs112967046

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445499	SCV000537018	uncertain significance	Monogenic diabetes	2016-07-22	criteria provided, single submitter	research	ACMG Criteria: PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV001351930	SCV001546447	uncertain significance	not provided	2025-02-01	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 685 of the WFS1 protein (p.Arg685Cys). This variant is present in population databases (rs112967046, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 34789499). ClinVar contains an entry for this variant (Variation ID: 393391). 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.
GeneDx	RCV001351930	SCV001940168	uncertain significance	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Reported with a second variant (phase unknown) in a patient clinically suspected to have monogenic diabetes in published literature (Colclough et al., 2021); 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: 11920861, 34789499)
3billion, Medical Genetics	RCV004668975	SCV002521266	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	2024-07-30	criteria provided, single submitter	clinical testing	The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v4.0.0 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Different missense changes at the same codon (p.Arg685His, p.Arg685Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045446, VCV000215395 / PMID: 18518985). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816668	SCV005073522	uncertain significance	Optic atrophy	2021-01-01	criteria provided, single submitter	clinical testing
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV002250628	SCV005073827	pathogenic	Wolfram syndrome 1	2024-06-13	criteria provided, single submitter	research	Homozygosity of a very rare variant predicted deleterious by most prediction programs and classified as likely pathogenic by one CLinVar entry.
Fulgent Genetics, Fulgent Genetics	RCV005033963	SCV005667528	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529580	SCV004112224	uncertain significance	WFS1-related disorder	2024-04-30	no assertion criteria provided	clinical testing	The WFS1 c.2053C>T variant is predicted to result in the amino acid substitution p.Arg685Cys. This variant has been reported in the compound heterozygous state along with a truncating variant in a patient with features consistent with Wolfram syndrome (Table S4 and S8, Colclough et al. 2022. PubMed ID: 34789499). This variant was also reported in a study of the relationship between Wolfram syndrome carrier status and suicide (Crawford et al. 2002. PubMed ID: 11920861). A different substitutions at the same codon have been reported in patients with sensorineural hearing loss or early-onset diabetes (p.Arg685Pro, Bramhall et al. 2008. PubMed ID: 18518985; p.Arg685His, Artuso et al. 2015. PubMed ID: 25048417). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004567928	SCV005049976	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research