rs199946797

Description

Observed in apparent homozygous state in multiple patients with early-onset diabetes with or without other features of Wolfram syndrome, supporting the conclusion that R558C causes a mild form of Wolfram syndrome, with later onset of diabetes (17.8 +/- 8.3 years) and absence of optic atrophy in most homozygous individuals of Ashkenazi Jewish ancestry (Bansal et al., 2018); Observed in heterozygous state in an individual with ataxia and in an individual with familial schizophrenia (Fogel et al., 2014; Torres et al., 2001), however it is unclear whether the variant contributed to these individuals' phenotypes; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25133958, 21446023, 28432734, 24890733, 31264968, 30014265, 27395765, 26435059, 17568405, 29207974, 30245029, 22226368, 30957632, 12754709, 15277431, 19344068, 32518033, 32335055, 33046911, 34556497, 31980526, 33763535, 11244483)

PS1 PM2 PP3 PP4

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 558 of the WFS1 protein (p.Arg558Cys). This variant is present in population databases (rs199946797, gnomAD 1.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of Wolfram syndrome (PMID: 17568405, 21446023, 23596069, 27395765, 28432734, 29207974, 30014265, 30957632). ClinVar contains an entry for this variant (Variation ID: 198835). 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 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.

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.

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.