Submissions for variant NM_006005.3(WFS1):c.1886G>A (p.Arg629Gln)

gnomAD frequency: 0.00006  dbSNP: rs146670741

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038647	SCV000062325	likely pathogenic	Rare genetic deafness	2013-08-06	criteria provided, single submitter	clinical testing	The Arg629Gln variant in WFS1 has not been reported in the literature nor previo usly identified by our laboratory in any other families. Another variant at the same locus, Arg629Trp has been reported in 3 individuals with Wolfram syndrome i n the homozygous and compound heterozygous state, and in 4 heterozygous carriers , only one of whom is reported to have hearing loss (Kadayifci 2001, Hoffmann 20 03). Additionally, functional studies have shown that the Arg629Trp variant lead s to instability of the protein (Hoffman 2003). However, this in vitro assay may not accurately represent biological function. Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg629Gln variant may not impact the protein, though this information i s not predictive enough to rule out pathogenicity. The Arg629Gln variant has bee n identified in 0.01% (1/8600) of European American chromosomes in a broad popul ation by the NHLBI Exome sequencing project, and 0.1% (2/2178) of chromosomes fr om the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; dbSNP rs14667074 1). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In summary, this variant is l ikely pathogenic, though additional studies are required to fully establish its clinical significance.
GeneDx	RCV000196272	SCV000252534	uncertain significance	not provided	2020-09-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174425	SCV001337563	uncertain significance	Monogenic diabetes	2018-01-05	criteria provided, single submitter	research	ACMG criteria: PP3 (4 predictors), BP4 (6 predictors), PM5 ([ p.Arg629Trp, rs71530910 pathogenic with PS4 (PMIDs:11811080, 25173644, 27468121, and 12913071), PP1 mod (same PMIDs), PP3 (3 predictors), PS3 (PMID: 12913071)=pathogenic]=VUS, high priority
Invitae	RCV000196272	SCV002183901	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 45443). 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. This variant disrupts the p.Arg629 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11811080, 12913071, 27468121, 30957632, 31600780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt WFS1 protein function. This variant has not been reported in the literature in individuals affected with WFS1-related conditions. This variant is present in population databases (rs146670741, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 629 of the WFS1 protein (p.Arg629Gln).
Ambry Genetics	RCV002513507	SCV003717477	uncertain significance	Inborn genetic diseases	2021-07-22	criteria provided, single submitter	clinical testing	Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome or WFS1-related low-frequency sensorineural hearing loss (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003125863	SCV003802950	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 rs146670741 in Wolfram's syndrome yet.