CALM3 – Long QT Syndrome

CALM3 has been implicated in long QT syndrome through multiple independent studies that have identified pathogenic missense variants in patients presenting with severe cardiac arrhythmias. The collective evidence comprises several unrelated probands, with findings that include multi-family segregation and recurrent detection across independent cohorts (PMID:26969752).

The genetic evidence indicates an autosomal dominant mode of inheritance. Case series and cohort studies have identified CALM3 variants—among them the variant c.426T>G (p.Phe142Leu)—in probands with long QT syndrome. These variants disrupt conserved residues critical to the protein’s function, reinforcing the gene’s role in the condition (PMID:26969752).

Familial studies have demonstrated segregation of mutant alleles with disease phenotypes, with additional affected relatives noted in select cases. Such segregation, although noted in a limited number of affected family members, further bolsters the credibility of the association between CALM3 alterations and the long QT phenotype.

Detailed case series have reported that CALM3 variants, including the representative c.426T>G (p.Phe142Leu), are associated with early-onset and severe manifestations of long QT syndrome. The variant spectrum predominantly consists of missense changes that perturb calmodulin’s essential Ca2+-binding properties, which are fundamental for proper cardiac contractility (PMID:26969752).

Functional studies provide strong experimental confirmation of the deleterious impact of these variants. In vitro assays and animal model experiments have demonstrated that mutant calmodulin exhibits impaired Ca2+ binding and defective regulation of key cardiac ion channels, such as the L-type Ca2+ channel. These findings provide a clear mechanistic link between CALM3 dysfunction and the electrophysiological abnormalities observed in long QT syndrome (PMID:27516456).

In summary, the robust integration of genetic data and functional studies underscores a strong gene-disease association for CALM3 in long QT syndrome. The evidence supports its clinical utility not only for diagnostic decision-making but also for tailoring precision therapies in affected patients. Key take‑home: CALM3 variant analysis should be an integral part of the molecular workup in patients with suspected long QT syndrome to inform risk assessment and therapeutic strategies.

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. Arrhythmia and electrophysiology • 2016 • Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks PMID:27516456

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