ClinVar

Description

The CLCN1 c.1453A>G (p.Met485Val) missense variant has been reported in at least six studies in which it is found in a total of 13 individuals with myotonia congenita, including two in a homozygous state, ten in a compound heterozygous state (including two siblings) and one proband with unspecified zygosity (Meyer-Kleine et al. 1995; Fialho et al. 2007; Mazon et al. 2012; Skálová et al. 2013; Brugnoni et al. 2013; Hoche et al. 2014). The variant has also been reported in a heterozygous state in at least three unaffected relatives (Meyer-Kleine et al. 1995; Hoche et al. 2014). The p.Met485Val variant was absent from 200 control alleles but is reported at a frequency of 0.000773 in the Other population of the Genome Aggregation Database. Functional studies involving expression in Xenopus oocytes demonstrated that the variant led to a drastic reduction of the single channel conductance compared to wildtype (Wollnik et al. 1997). Based on the evidence, the p.Met485Val variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.