ClinVar

Description

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.