Calmodulin is a calcium-binding protein that is essential for multiple intracellular processes including modulation of cardiac ion channels. An exactly identical calmodulin protein is encoded by 3 separate genes, CALM1-3, located on different chromosomes (14, 2 and 19, respectively). In 2013 Crotti et al. were the first to identify de-novo missense variants in CALM1 and CALM2 in 2 patients with a unique phenotype (PMID 23388215). Both were infants presenting with marked QT prolongation, life-threatening ventricular arrhythmias and intermittent AV block. Subsequent studies identified multiple similar cases with de-novo variants in one of the 3 CALM genes. Based on this evidence the Expert Panel classified all calmoudulin genes (CALM1-3) as having a 'Definitive' level of evidence for disease causation of LQTS with atypical features presenting in childhood. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams were reviewed by the LQTS Clinical Domain Expert Panel. For a detailed discussion of this group's work and the separate scores of the 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
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