CALM3
protein-codingcalmodulin 3, the group of Receptor ligands|Phosphorylase kinase subunits|EF-hand domain containing
Gene summary
This gene encodes a member of a family of proteins that binds calcium and functions as a enzymatic co-factor. Activity of this protein is important in the regulation of the cell cycle and cytokinesis. Multiple alternatively spliced transcript variants have been observed at this gene. [provided by RefSeq, Aug 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~9.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: ClinGen
CALM3 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). The CALM3 gene is located on chromosome 19 and encodes for calmodulin 3, a 149 amino acid protein that is identical in sequence to two other calmodulin genes (CALM1 on chromosome 14 and CALM2 on chromosome 2). All three CALM genes have been classified as Definitive for Long QT syndrome by the LQTS Gene Curation Expert Panel, noting that these genes tend to be associated with atypical features of LQTS (presentation in infancy or early childhood and with heart block and severe QT prolongation). The CALM genes have also been associated with CPVT phenotypes although less evidence has thus far been published for CPVT compared to LQTS. Evidence for the association of CALM genes to CPVT comes from the International Calmodulin Registry study (Crotti et al, 2019, PMID:31170290) and other genetic and experimental studies. Genetic evidence for the association of CALM3 with CPVT comes from an apparently de novo case in the Registry with the p.Asp132Glu variant - the same variant in the CALM2 gene was also detected de novo in a patient with mixed features of CPVT and LQTS (Crotti et al, 2019, PMID:31170290). The p.Ala103Val variant was detected in a CPVT patient with its pathogenicity supported by functional evidence (Gomez-Hurtado et al, 2016, PMID:27516456). Based on this genetic and experimental evidence, CALM3 scored with limited evidence of association with CPVT but was upgraded to a Moderate classification by the expert panel. However, the expert panel unanimously agreed that, the despite this classification and the modest amount of published evidence linking CALM3 variants with a CPVT phenotype, all three CALM genes have unequivocal evidence for causation of isolated CPVT, in addition to LQTS and hybrid phenotypes. The three CALM genes encode for identical proteins which are all expressed in heart tissue, and multiple identical variants in two or more of the CALM genes have been shown to cause the same phenotypes, e.g. the de novo variant p.Asp130Gly has been shown in all 3 CALM genes to provoke LQTS in children, which demonstrates the functional similarity of these genes/proteins. Collectively, the three CALM genes would have strong/definitive evidence for association with CPVT. CALM3 has previously been classified as a definitive gene for atypical LQTS, unambiguously demonstrating the pathogenicity of this gene for inherited arrhythmia syndromes. Finally, as described above, multiple patients with CALM3 variants have been shown to present with a classical CPVT phenotype. Therefore this gene should be included in CPVT genetic testing panels. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: ClinGen
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”
Inheritance Pattern: AD
Disease ID:MONDO:0032915
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0032915
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0019171
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Individuals may present with severe cardiac manifestations, including arrhythmias, syncope, and sudden death, and surveillance, preventive measures (eg, including avoidance of dangerous or excacerbating factors), and treatment (eg, including medical treatment or ICD placement, which have both been described as beneficial in affected individuals) may allow early and beneficial management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CALM3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005184.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 63 | 1 | 65 | ||
| missense | 4 | 6 | 36 | 46 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 4 | 6 | 42 | 63 | 1 | 116 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005175.2 | 6 | MANE Select | |
| Ensembl | ENSP00000291295.8 | 6 | MANE Select | |
| RefSeq | NP_001316850.1 | 4 | Standard | |
| RefSeq | NP_001316851.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
- Aldosterone synthesis and secretion - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Pertussis - Homo sapiens (human)
Biological Process
- G2/M transition of mitotic cell cycle
- response to amphetamine
- regulation of heart rate
- detection of calcium ion
- G protein-coupled receptor signaling pathway
Molecular Function
- calcium ion binding
- protein binding
- adenylate cyclase binding
- adenylate cyclase activator activity
- protein kinase binding
Cellular Component
- spindle pole
- nucleus
- cytoplasm
- centrosome
- spindle microtubule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000291295
- Coding exons
- 6
- Length
- 9720
- Individuals with no LoFs
- 125651
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125652
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.98 | 9 | 87.3 | 0.103 | 0.00000470 | 1011 |
| Missense (PolyPhen) | 1 | 18.614 | 0.053722 | 259 | ||
| Synonymous | -0.180 | 34 | 32.7 | 1.04 | 0.00000201 | 251 |
| Loss of Function | 2.68 | 0 | 8.38 | 0.00 | 4.40e-7 | 98 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis. {ECO:0000250|UniProtKB:P0DP23, ECO:0000269|PubMed:16760425}.;
- Disease
- DISEASE: Note=Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare condition caused by mutation in CALM3 that lead to an arrhythmogenic disorder characterized by stress- induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. {ECO:0000269|PubMed:27516456}.;
Recessive Scores
- pRec
- 0.935
Intolerance Scores
- LoFtool
- 0.475
- RVIS EVS
- -0.1
- RVIS percentile EVS
- 46.2
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.868