rs71530923

rs71530923, also known as c.124C>T, p.Arg42Ter, R42* and R42X, represents a rare variant in the WFS1 gene on chromosome 4. A lab report in ClinVar indicates the minor allele is an autosomal recessive causative for Wolfram syndrome, and that when heterozygous, is pathogenic for a form of diabetes mellitus that includes increased risk for deafness. The summary evidence provided in ClinVar states the following: The Arg42X variant in WFS1 has not been previously identified in individuals with Wolfram syndrome, but has been identified in 0.02% (1/8540) of European American chromosomes by the NHLBI Exome Sequencing Project (evs.gs.washington.edu; dbSNP rs71530923). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a pathogenic interpretation. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus (Ohata 1998, Sandhu 2007, Franks 2008). In summary, this variant meets our criteria to be classified as pathogenic (pcpgm.partners.org).