ClinVar

For discussion of the arg894-to-ter (R894X) mutation in the CLCN1 gene that was found in compound heterozygous state in sibs with autosomal recessive myotonia congenita (255700) by Pusch et al. (1995), see 118425.0010.

In patients with both autosomal recessive and autosomal dominant (160800) myotonia congenita, Meyer-Kleine et al. (1995) identified a mutation in the CLCN1 gene, resulting in an R894X substitution. Functional expression of the R894X mutant in Xenopus oocytes revealed a large reduction, but not complete abolition, of chloride currents. Further, it had a weak dominant-negative effect on wildtype currents in coexpression studies. Reduction of currents predicted for heterozygous carriers were close to the borderline value, sufficient to elicit myotonia.

Sun et al. (2001) found a carrier frequency of 0.87% for the R894X mutation in the northern Scandinavian population.

In a French Canadian family with myotonia, Dupre et al. (2009) found that the R894X mutation could be expressed in a semidominant or recessive manner. The proband, who was heterozygous for the R894X mutation, had muscle stiffness and mild warm-up phenomenon, but no significant percussion myotonia and no myotonia on EMG. In contrast, her daughters, who were compound heterozygous for the R894X and R300X (118425.0017) mutations, showed a moderately severe phenotype with generalized hypertrophy consistent with autosomal recessive Becker myotonia. This compound heterozygous genotype showed resistance to phenytoin, mexiletine, and quinine.

Proband also has heterozygous pathogenic CLCN1 p.Pro480HisfsTer24 frameshift variant (not confirmed in trans).