ClinVar

Description

The CLCN1 c.1437_1450delACCCTGCGGAGGCT (p.Pro480HisfsTer24) variant results in a frameshift variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Pro480HisfsTer24 variant has been reported in at least 14 individuals with myotonia congenita (MC), which includes three in a homozygous state and six in a compound heterozygous state (Meyer-Kleine et al. 1994; Lehmann-Horn et al. 1995; Meyer-Kleine et al. 1995; Mailander et al. 1996; Fialho et al. 2007; Dupre et al. 2009; Raja Rayan et al. 2012; Brugnoni et al. 2013). The variant appears to be associated with an autosomal recessive inheritance pattern, as the majority of evaluated heterozygous family members were unaffected. However, a single clinically unaffected heterozygous male was reported to display latent myotonia (Mailander et al. 1996). Homozygosity for the variant also reportedly results in a more severe phenotype associated with transient weakness and severely reduced chloride conductance in muscle fibers, consistent with features of recessive MC. The p.Pro480HisfsTer24 variant was absent from at least 660 control chromosomes and is reported at a frequency of 0.000150 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence, the p.Pro480HisfsTer24 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.