Submission Details

CALM1 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). The CALM1 gene is located on chromosome 14 and encodes for calmodulin 1, a 149 amino acid protein that is identical in sequence to two other calmodulin genes (CALM2 on chromosome 2 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 CALM1 comes from a study that described familial CPVT cases. The p.Asn54Ile variant segregated with disease in a large family pedigree (Nyegaard et al, 2012, PMID:23040497), with a second family with this variant described in the Registry (Crotti et al, 2019, PMID:31170290). The p.Asn98Ser variant occurred de novo in a proband with CPVT (Nyegaard et al, 2012, PMID:23040497) - the same p.Asn98Ser variant was detected de novo in CALM2 in a CPVT patient (Jiménez-Jáimez et al, 2016, PMID:27100291). These variants have also been studied experimentally and shown to cause CPVT-like phenotypes in zebrafish (Sondergaard et al, 2015, PMID:25557436) and mouse models (Tsai et al, 2020, PMID:32929985) and in non-patient cellular assays (Hwang et al, 2014, PMID:24563457; Søndergaard et al, 2015, PMID:26309258). A family with the CALM1 p.Ile53Val variant has also been investigated in Toronto (as yet unpublished and therefore not scored during this curation). The affected father and two children carried the variant - all had structurally normal hearts and PVCs during exercise and the children suffered cardiac arrests at the ages of 12 while swimming and 18 while dancing (no other relevant variants were found in a broad 147 gene panel). Based on this genetic and experimental evidence, CALM1 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 CALM1 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. CALM1 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 CALM1 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).