Submissions for variant NM_006005.3(WFS1):c.2122C>T (p.Arg708Cys)

gnomAD frequency: 0.00016  dbSNP: rs200099217

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000585352	SCV000337893	uncertain significance	not provided	2015-12-02	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445375	SCV000537019	uncertain significance	Monogenic diabetes	2015-12-16	criteria provided, single submitter	research	ACMG Criteria: PP3
CeGaT Center for Human Genetics Tuebingen	RCV000585352	SCV000693145	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000585352	SCV001796221	uncertain significance	not provided	2020-11-23	criteria provided, single submitter	clinical testing	Reported previously in the heterozygous state in an individual with Wolfram syndrome who was also apparently homozygous for a WFS1 frameshift variant (Tessa et al., 2001).; Reported previously as a variant identified at a low frequency in individuals with type 1 diabetes (Awata et al., 2013); however, additional details were not provided to support the potential pathogenicity of this variant; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31264968, 23856252, 15368487, 20972738, 11295831, 26435059, 18688868)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000585352	SCV002280011	likely pathogenic	not provided	2024-01-27	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 708 of the WFS1 protein (p.Arg708Cys). This variant is present in population databases (rs200099217, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 11295831, 31264968; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 285046). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002494843	SCV002776599	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-04-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535338	SCV004117168	uncertain significance	WFS1-related disorder	2023-09-08	criteria provided, single submitter	clinical testing	The WFS1 c.2122C>T variant is predicted to result in the amino acid substitution p.Arg708Cys. This variant was reported in the heterozygous state in a patient with Wolfram syndrome, and was described as ‘probably neutral’ due the patient being homozygous for a different pathogenic premature termination variant (Tessa. 2001. PubMed ID: 11295831). This variant has also been described in a patient with type 1 diabetes (Table S6, Yu. 2019. PubMed ID: 31264968). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6303644-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004021170	SCV004979918	uncertain significance	Inborn genetic diseases	2022-06-28	criteria provided, single submitter	clinical testing	Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.