CALML2; CAMI; CPVT4; DD132; LQT14; PHKD; caM
The CALM1 gene is associated with autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT) (MedGen UID: 766961) and long QT syndrome (LQTS) (PMID: 23388215).
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Pathogenic CALM1 variants are a rare cause of CPVT and LQTS.
CALM1 is one of several genes that encodes 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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|