Submissions for variant NM_006005.3(WFS1):c.2494C>T (p.Arg832Cys)

gnomAD frequency: 0.00016  dbSNP: rs148089728

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001700452	SCV002004963	uncertain significance	not provided	2023-03-02	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: 26435059, 31264968)
Invitae	RCV001700452	SCV002277365	uncertain significance	not provided	2023-10-06	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 832 of the WFS1 protein (p.Arg832Cys). This variant is present in population databases (rs148089728, gnomAD 0.03%). 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: 592097). 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 expected to disrupt 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.
Fulgent Genetics, Fulgent Genetics	RCV002485847	SCV002789647	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-04-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535807	SCV004116149	uncertain significance	WFS1-related disorder	2023-09-18	criteria provided, single submitter	clinical testing	The WFS1 c.2494C>T variant is predicted to result in the amino acid substitution p.Arg832Cys. This variant was reported in an individual with type 1 diabetes (Yu et al 2019. PubMed ID: 31264968). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6304016-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723288	SCV000854677	uncertain significance	Cataract 41	2018-05-11	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700452	SCV001923584	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001700452	SCV001963124	uncertain significance	not provided		no assertion criteria provided	clinical testing