ClinVar

Description

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.