ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1886G>A (p.Arg629Gln) (rs146670741)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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

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