ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1672C>T (p.Arg558Cys) (rs199946797)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255189 SCV000232696 likely pathogenic not provided 2015-01-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000599628 SCV000271294 uncertain significance not specified 2017-09-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg558Cys variant in WFS1 has been previously reported in the homozygous or compound hete rozygous state in 5 individuals with Wolfram syndrome, at least 3 of whom were r eported to have late onset disease (Cano 2007, Chaussenot 2011, Lieber 2012, Cha ussenot 2015, Astuti 2017, Oakley 2017). It has also been identified in at least 2 individuals with nonsyndromic optic atrophy and 1 individual with progressive cerebellar ataxia (Fogel 2014, Grenier 2016, Sharma 2017). Additionally, our la boratory has identified the p.Arg558Cys variant in the heterozygous state in 2 i ndividuals with apparently nonsyndromic hearing loss, 1 of whom had an alternate explanation for their hearing loss. In vitro functional studies and in silico p rediction tools provide some evidence that the variant may impact protein functi on (Qian 2015, Sharma 2017); however, these types of assays may not accurately r epresent biological function. This variant has been identified in 1.4% (140/1015 0) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database, including 1 homozygous individual (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1999 46797). It should be noted that the gnomAD database may include individuals with late onset or adult disease such as diabetes mellitus and psychiatric disorders (http://gnomad.broadinstitute.org/about). In summary, while there is some suspi cion for a pathogenic role, because of its high frequency in the Ashkenazi Jewis h population and limited functional data, the clinical significance of this vari ant is uncertain.
GeneDx RCV000255189 SCV000322006 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing The R558C variant in the WFS1 gene has been reported previously as a pathogenic variant in both the compound heterozygous and homozygous state in individuals with features of Wolfram syndrome (Cano et al., 2007, Lieber et al., 2012, Chaussenot et al, 2011). The R558C variant has also been reported as a variant of uncertain significance in an individual with ataxia and polyneuropathy and in an individual with familial schizophrenia (Fogel et al., 2014; Torres et al., 2001). The Human Gene Mutation Database reports R558C to be a functional polymorphism (Stenson et al., 2014). The variant is observed in 29/126622 (0.0229%) alleles from individuals of European background, and in 140/10150 (1.3793%) alleles from individuals of Ashkenazi Jewish background, in large population cohorts; additionally, one homozygote has been observed in the global population (Lek et al., 2016). An unaffected homozygote has also been observed at GeneDx. The R558C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We consider this variant to be of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000501459 SCV000597980 likely pathogenic Wolfram syndrome 2016-05-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778739 SCV000915097 pathogenic WFS1-Related Spectrum Disorders 2018-10-10 criteria provided, single submitter clinical testing The WFS1 c.1672C>T (p.Arg558Cys) missense variant has been reported in at least seven studies and is found in a total of 15 individuals with Wolfram syndrome, including in a homozygous state in at least ten individuals, in a compound heterozygous state in two, and in a heterozygous state in three individuals (Cano et al. 2007; Ganie et al. 2009; Chaussenot et al. 2011; Lieber et al. 2012; Chaussenot et al. 2015; Grenier et al. 2016; Bansal et al. 2018). The variant was also reported in a heterozygous state in one individual with schizophrenia (Torres et al. 2001) and in another individual with cerebellar ataxia (Fogel et al. 2014). The p.Arg558Cys is identified with a very mild phenotype that authors indicate may be difficult to diagnose clinically (Bansal et al. 2018). The p.Arg558Cys variant was found in 58 alleles from 2589 control sample and is reported at a frequency of 0.00084 in the European (non-Finnish) population of the Exome Aggregation Consortium and 0.013790 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Arg558Cys variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000255189 SCV001559490 uncertain significance not provided 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 558 of the WFS1 protein (p.Arg558Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199946797, ExAC 0.08%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with clinical features of Wolfram syndrome (PMID: 30957632, 17568405, 21446023). ClinVar contains an entry for this variant (Variation ID: 198835). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg558 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15277431, 31567480). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Constantin Polychronakos Laboratory,The Research Institute of the McGill University Health Centre RCV001175325 SCV001250642 pathogenic Diabetes mellitus no assertion criteria provided research PS1 PM2 PP3 PP4

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