CALR3
protein-codingcalreticulin 3
Gene summary
The protein encoded by this gene belongs to the calreticulin family, members of which are calcium-binding chaperones localized mainly in the endoplasmic reticulum. This protein is also localized to the endoplasmic reticulum lumen, however, its capacity for calcium-binding may be absent or much lower than other family members. This gene is specifically expressed in the testis, and may be required for sperm fertility. Mutation in this gene has been associated with familial hypertrophic cardiomyopathy. [provided by RefSeq, Dec 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0024573
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0005045
Submitter: ClinGen
CALR3 was first associated with hypertrophic cardiomyopathy (HCM) in 2007 (Chiu et al, PMID 17655857). However, these 2 unique variants from the 2 probands in this publication now show no evidence to support the association of CALR3 with HCM. This is due to one variant reported in a proband with 2 missense variants in MYBPC3, and the other variant being seen frequently in control populations. Both variants have no experimental evidence to support their pathogenicity. There is no additional case evidence. The mechanism for disease is unknown. There is no experimental evidence to support the gene-disease association. There is new contradictory evidence. One publication showed CALR3 did not segregate with disease in some families, a large proportion of probands with CALR3 variants had at least 1 VUS in another cardiomyopathy gene, no significant difference in a case-control study, and that CLAR3 protein was not expressed in human myocardial tissue (Verhagen et al, 2018, PMID 29988065). Two previous publications also shown no cardiac expression and no cardiac abnormalities in CALR3 knockout animal models (Ikawa et al, 2011, PMID 21131354; Hung et al, 2013, PMID 23873374). In summary, the evidence to support the gene-disease association between CALR3 and HCM is disputed. This is due to a lack of supportive evidence since the previous curation and new convincing evidence has emerged that contradicts the gene-disease association. This gene-disease association was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on February 7, 2017. It was reevaluated on January 11th, 2023. As a result of this reevaluation, the classification changed from limited to disputed.
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Surveillance (eg, including echocardiography) for manifestations can allow early diagnosis, preventive measures relating to disease sequelae, and prompt treatment, which may reduce morbidity and mortality
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CALR3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_145046.5. 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 | 74 | 4 | 79 | ||
| missense | 171 | 16 | 2 | 189 | ||
| nonsense | 7 | 7 | ||||
| start loss | 3 | 3 | ||||
| frameshift | 1 | 13 | 14 | |||
| splice donor/acceptor (+/-2bp) | 6 | 1 | 7 | |||
| Total | 0 | 1 | 201 | 91 | 6 | 299 |
Highest pathogenic variant AF is 0.00012578009
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_659483.2 | 9 | MANE Select | |
| Ensembl | ENSP00000269881.3 | 9 | MANE Select | |
| Ensembl | ENSP00000471533.1 | 4 | Standard | |
| Ensembl | ENSP00000602523.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| calr3a | Danio rerio | Structure: neuromast Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- protein folding
- spermatogenesis
- biological_process
- cell differentiation
Molecular Function
- calcium ion binding
- carbohydrate binding
- protein folding chaperone
- unfolded protein binding
Cellular Component
- nuclear envelope
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000269881
- Coding exons
- 9
- Length
- 17136
- Individuals with no LoFs
- 125683
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125748
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.353 | 195 | 209 | 0.931 | 0.0000117 | 2561 |
| Missense (PolyPhen) | 68 | 80.621 | 0.84345 | 1028 | ||
| Synonymous | -0.215 | 87 | 84.5 | 1.03 | 0.00000581 | 650 |
| Loss of Function | 1.05 | 17 | 22.4 | 0.760 | 0.00000117 | 246 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00018 | rare |
| Latino/Admixed American | 0.00032 | 0.00032 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00035 | 0.00035 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: During spermatogenesis, may act as a lectin-independent chaperone for specific client proteins such as ADAM3. Required for sperm fertility (By similarity). CALR3 capacity for calcium- binding may be absent or much lower than that of CALR. {ECO:0000250, ECO:0000269|PubMed:21590275}.;
- Disease
- DISEASE: Cardiomyopathy, familial hypertrophic 19 (CMH19) [MIM:613875]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. {ECO:0000269|PubMed:17655857}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.918
- RVIS EVS
- 0.15
- RVIS percentile EVS
- 64.74
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.883
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |