CaM; CaMIII; HEL-S-72; PHKD; PHKD3
The CALM3 gene is associated with autosomal dominant long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 25460178).
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Pathogenic CALM3 variants are a rare cause of LQTS and CPVT.
CALM3 is one of several genes that encode calmodulin, a calcium-binding protein involved in intracellular signaling.
CALM1, CALM2, CALM3
OMIM: 114180, 114182, 114183
The CALM1, CALM2, and CALM3 genes are associated with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) and long QT syndrome (LQTS).
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a cardiac arrhythmia condition affecting the electrical system of the heart. CPVT is characterized by bidirectional or polymorphic ventricular tachycardia induced by acute adrenergic activation in individuals with structurally normal hearts.
Long QT syndrome (LQTS) is a cardiac arrhythmia condition that primarily affects the electrical system of the heart. LQTS is defined by a prolonged QTc interval and T wave abnormalities on an ECG without the presence of any known structural heart disease. Individuals with LQTS can develop a specific abnormal heart rhythm called Torsade de pointes (TdP).
Most reports of calmodulin-related disease have been severe with early, childhood-onset. However, cascade screening has identified older and asymptomatic relatives with prolonged QT intervals. Some patients have also presented with overlapping features of LQTS and CPVT.
The abnormal heart beats in the above arrhythmia conditions can lead to palpitations, dizziness (pre syncope), fainting (syncope), seizure-like activity and sudden cardiac arrest/death including sudden infant death syndrome (SIDS). Symptoms may be triggered by exercise, acute emotion, homeostatic imbalance, and/or the use of certain medications.
The CALM genes each encode an identical calcium binding protein called calmodulin which is expressed in cardiac muscle cells. Calmodulin is a subunit of phosphorylase kinase and plays a role in signaling pathways, cell cycle progression and proliferation by mediating the control of a large number of enzymes, ion channels, aquaporins and other proteins.
Pathogenic variants in the CALM genes have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring. Variants may be inherited or occur de novo. Penetrance and expressivity have not been well studied in calmodulin-related arrhythmias, although reduced penetrance and variable expressivity have been reported.
Arrhythmias are recommended to be managed depending on clinical presentation with options including lifestyle modification, medication, surgical, and device therapy. Genetic testing may help elucidate specific triggers or predisposition to early age of onset.
Review date: March 2017
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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