ClinVar

In a 35-year-old Caucasian woman, born of unrelated parents (family 2), with classic congenital myopathy-22A (CMYP22A; 620351), Zaharieva et al. (2016) identified compound heterozygous mutations in the SCN4A gene: a c.673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a c.3628G-T transversion, resulting in a cys1209-to-phe (C1209F; 603967.0035) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the ExAC database. Electrophysiologic studies in HEK293 cells transfected with the mutations showed that R225W was a hypomorphic allele causing reduced current amplitude, whereas C1209F resulted in a complete loss of channel function. The patient showed moderate hypotonia at birth requiring early respiratory support, delayed motor milestones, and proximal muscle weakness, but she did not have limb contractures and was ambulatory with a slow waddling gait. Her motor skills improved during childhood, but began to deteriorate around age 30. Her carrier parents were clinically unaffected.

Zaharieva et al. (2016) noted that Lee et al. (2009) had identified a heterozygous R225W mutation in a 21-year-old Korean man (patient 3) with mild nonpainful paramyotonia congenita (PMC; 168300). R225W is located at the cytoplasmic side of transmembrane S3 segment of domain I.