CALM3 – Familial long QT syndrome

Autosomal dominant familial long QT syndrome (LQTS) is a life-threatening channelopathy characterized by QT interval prolongation and risk of syncope, cardiac arrest, and sudden death. CALM3 (HGNC:1449) encodes one of three identical calmodulin proteins critical for calcium signaling in cardiomyocytes. Pathogenic missense variants in CALM3 cluster in EF-hand domains, abrogate Ca2+ binding, and dominantly dysregulate voltage-gated calcium channels, leading to delayed repolarization and arrhythmia.

Genetic evidence for CALM3-related LQTS includes multiple de novo and inherited missense variants in unrelated patients. A cohort study of genetically elusive LQTS identified CALM3 c.426T>G (p.Phe142Leu) in two cases, with functional assays showing an 11-fold reduction in Ca2+ affinity and loss of CaV1.2 inactivation (PMID:26969752).

Segregation analysis demonstrated co-segregation of a novel CALM3 variant in a four-generation family: 14 carriers of p.Asn138Lys exhibited prolonged QTc, syncope, and two sudden deaths, confirming autosomal dominant inheritance (PMID:35225649). Somatic mosaicism for CALM3-E141K and D130G was documented in parents of affected offspring, underscoring variable expressivity and recurrence risk (PMID:31454269).

Functional assessment across models—including human cardiomyocytes and zebrafish—revealed that CALM3 variants such as p.Phe142Leu and p.Asp130Gly impair Ca2+ binding, decelerate L-type Ca2+ current inactivation, and provoke arrhythmogenic calcium waves, providing mechanistic concordance with human arrhythmia (PMID:26969752).

A population-based study in 6,161 Danes found that common CALM3 variants previously linked to congenital LQTS do not measurably affect QTc, syncope incidence, or mortality, distinguishing rare pathogenic CALM3 mutations from benign polymorphisms (PMID:26159999).

Collectively, CALM3 meets ClinGen Strong criteria for gene-disease association: multiple unrelated probands with de novo and familial missense variants, robust segregation in a large pedigree, and convergent functional data. CALM3 testing is warranted in genotype-negative LQTS cases, especially with early onset or severe arrhythmia.

Key Take-home: Rare CALM3 missense variants cause autosomal dominant familial LQTS by a dominant-negative impairment of Ca2+ binding and channel regulation, informing genetic diagnosis and management.

References

• Circulation. Cardiovascular genetics • 2016 • Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. PMID:26969752
• Circulation. Genomic and precision medicine • 2019 • Genetic Mosaicism in Calmodulinopathy. PMID:31454269
• Circulation. Arrhythmia and electrophysiology • 2022 • Novel CALM3 Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family. PMID:35225649
• European heart journal • 2015 • Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. PMID:26159999

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