Submission Details

CALM3 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). The CALM3 gene is located on chromosome 19 and encodes for calmodulin 3, a 149 amino acid protein that is identical in sequence to two other calmodulin genes (CALM1 on chromosome 14 and CALM2 on chromosome 2). All three CALM genes have been classified as Definitive for Long QT syndrome by the LQTS Gene Curation Expert Panel, noting that these genes tend to be associated with atypical features of LQTS (presentation in infancy or early childhood and with heart block and severe QT prolongation). The CALM genes have also been associated with CPVT phenotypes although less evidence has thus far been published for CPVT compared to LQTS. Evidence for the association of CALM genes to CPVT comes from the International Calmodulin Registry study (Crotti et al, 2019, PMID:31170290) and other genetic and experimental studies. Genetic evidence for the association of CALM3 with CPVT comes from an apparently de novo case in the Registry with the p.Asp132Glu variant - the same variant in the CALM2 gene was also detected de novo in a patient with mixed features of CPVT and LQTS (Crotti et al, 2019, PMID:31170290). The p.Ala103Val variant was detected in a CPVT patient with its pathogenicity supported by functional evidence (Gomez-Hurtado et al, 2016, PMID:27516456). Based on this genetic and experimental evidence, CALM3 scored with limited evidence of association with CPVT but was upgraded to a Moderate classification by the expert panel. However, the expert panel unanimously agreed that, the despite this classification and the modest amount of published evidence linking CALM3 variants with a CPVT phenotype, all three CALM genes have unequivocal evidence for causation of isolated CPVT, in addition to LQTS and hybrid phenotypes. The three CALM genes encode for identical proteins which are all expressed in heart tissue, and multiple identical variants in two or more of the CALM genes have been shown to cause the same phenotypes, e.g. the de novo variant p.Asp130Gly has been shown in all 3 CALM genes to provoke LQTS in children, which demonstrates the functional similarity of these genes/proteins. Collectively, the three CALM genes would have strong/definitive evidence for association with CPVT. CALM3 has previously been classified as a definitive gene for atypical LQTS, unambiguously demonstrating the pathogenicity of this gene for inherited arrhythmia syndromes. Finally, as described above, multiple patients with CALM3 variants have been shown to present with a classical CPVT phenotype. Therefore this gene should be included in CPVT genetic testing panels. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).