Submission Details

CALM2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). The CALM1 gene is located on chromosome 2 and encodes for calmodulin 2, a 149 amino acid protein that is identical in sequence to two other calmodulin genes (CALM1 on chromosome 14 and CALM3 on chromosome 19). 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 CALM2 with CPVT comes from two apparently de novo cases with the p.Glu46Lys variant in the Registry (Crotti et al, 2019, PMID:31170290). Another de novo case was described with the p.Asn98Ser variant (Jiménez-Jáimez et al, 2016, PMID:27100291) - the same p.Asn98Ser variant was detected de novo in CALM1 in a CPVT patient (Nyegaard et al, 2012, PMID:23040497). A de novo case with the p.Asp132Glu variant was detected in a patient with mixed features of CPVT and LQTS and was therefore scored less than the default (Makita et al, 2014, PMID:24917665) - the same p.Asp132Glu variant was also detected de novo in CALM3 in a CPVT patient (Crotti et al, 2019, PMID:31170290). As the p.Asn98Ser variant was also observed in CALM1 in a CPVT case, the experimental evidence demonstrating a CPVT phenotype for this variant from zebrafish models (Sondergaard et al, 2015, PMID:25557436) and non-patient cellular assays (Søndergaard et al, 2015, PMID:26309258) is also relevant for supporting the association of CALM2 with CPVT. Based on this genetic and experimental evidence, CALM2 scored with moderate evidence of association with CPVT. However, the expert panel unanimously agreed that, the despite this classification and the modest amount of published evidence linking CALM2 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. CALM2 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 CALM2 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).