ClinVar

In a 23-year-old Iraqi woman with catecholaminergic polymorphic ventricular tachycardia (CPVT4; 614916), Nyegaard et al. (2012) identified heterozygosity for a de novo 293A-G transition in exon 5 of the CALM1 gene, resulting in an asn97-to-ser (N97S) substitution at a highly conserved Ca(2+)-binding residue within the high-affinity binding-site III in the calmodulin C domain. The mutation was not found in her unaffected parents or in 500 Danish controls, and the patient was negative for mutation in 8 other arrhythmia-associated genes. At age 4 years, the patient underwent cardiac arrest due to ventricular fibrillation while running; she was stabilized by treatment with a beta-1 adrenergic receptor blocker. Electrocardiography (ECG) showed prominent U-waves in anterior leads but no evidence for long QT or Brugada syndromes. At 12 years of age, an off-medication exercise ECG demonstrated ventricular ectopy with couplets and triplets of varying morphology, which appeared to be bidirectional at times. At age 15, she suffered a second cardiac arrest and underwent implantation of an internal cardiac defibrillator (ICD). Functional analysis demonstrated that the mutant had significantly reduced Ca(2+) affinity compared to wildtype calmodulin. In addition, for the N97S mutant, calmodulin-RYR2 (180902) interaction was defective at low intracellular Ca(2+) concentrations and restored at moderate to high Ca(2+) concentrations.