ITPR3
protein-codinginositol 1,4,5-trisphosphate receptor type 3, the group of Protein phosphatase 1 regulatory subunits|Inositol 1,4,5-triphosphate receptors
Gene summary
This gene encodes a receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium. The receptor contains a calcium channel at the C-terminus and the ligand-binding site at the N-terminus. Knockout studies in mice suggest that type 2 and type 3 inositol 1,4,5-trisphosphate receptors play a key role in exocrine secretion underlying energy metabolism and growth. [provided by RefSeq, Aug 2010]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~76.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0015131
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0979570
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0859311
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0859311
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859311
Submitter: ClinGen
ITPR3: autosomal dominant demyelinating CMT (CMT1J) In the context of an autosomal dominant, demyelinating Charcot-Marie-Tooth (CMT1J) phenotype, ITPR3 was first described co-segregating in three affected individuals of one family by Schabhüttl et al. in 2014 (PMID:24627108). The same, recurrent variant has been replicated in another 9 families from different ancestries and one additional de-novo case by now (PMIDs: 39287469, 38938188). There are two more variants likewise co-segregating with a demyelinating CMT phenotype (PMID: 32949214). Within affected families, the authors observed a striking range in phenotype severity and disease onset. ITPR3 is a metabotropic calcium channel expressed in Schwann cells (PMIDs: 36444295, 38938188). Besides CMT, heterozygous missense variants in ITPR3 have been observed in a dominant immune disease with tooth infections (PMIDs: 39560673, 39270020), with neuropathy reported in some, but not extensively assessed in all patients. In transfected HEK293 cells, all CMT-associated variants resulted in elevated basal cytosolic Ca2+ levels, decreased endoplasmic reticulum Ca2+ store content, and constitutive store-operated Ca2+ entry in the absence of any stimuli, consistent with a leaky IP3R channel pore (PMID: 36444295). In Lancashire Heeler dogs, a spontaneous homozygous stop mutation led to a likewise demyelinating neuropathy phenotype associated with reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dogs’ fibroblasts (PMID: 39804930). In summary, strong clinical evidence, including a specific phenotype, variant recurrency, an overall LOD score of 5.71, and de-novo occurrence, is supported by experimental data on gene and variant level and has been replicated over time. We therefore classify the gene-disease relationship of ITPR3 and autosomal dominant, demyelinating CMT as definitive.
Inheritance Pattern: AD
Disease ID:MONDO:0859311
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015131
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0859311
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ITPR3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002224.4. 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 | 5 | 67 | 18 | 90 | ||
| missense | 3 | 5 | 438 | 18 | 4 | 468 |
| nonsense | 3 | 3 | ||||
| start loss | 0 | |||||
| frameshift | 7 | 7 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 14 | 15 | |||
| Total | 3 | 6 | 467 | 85 | 22 | 583 |
Highest pathogenic variant AF is 7.143939e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002215.2 | 58 | MANE Select | |
| Ensembl | ENSP00000475177.1 | 58 | MANE Select | |
| Ensembl | ENSP00000363435.4 | 58 | Standard | |
| Ensembl | ENSP00000363435.4 | 58 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| itpr3 | Danio rerio | Structure: whole organism Quality: decreased length abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
- Platelet activation - Homo sapiens (human)
- Cortisol synthesis and secretion - Homo sapiens (human)
- Aldosterone synthesis and secretion - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
Biological Process
- G protein-coupled receptor signaling pathway
- positive regulation of cytosolic calcium ion concentration
- memory
- platelet activation
- inositol phosphate-mediated signaling
Molecular Function
- inositol hexakisphosphate binding
- inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity
- calcium ion binding
- protein binding
- calcium-release channel activity
Cellular Component
- nuclear outer membrane
- nucleoplasm
- nucleolus
- cytoplasm
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000374316
- Coding exons
- 58
- Length
- 76210
- Individuals with no LoFs
- 125560
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 188
- Defined
- 125748
- p
- 0.000748
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.55 | 1144 | 1.67e+3 | 0.686 | 0.000111 | 17656 |
| Missense (PolyPhen) | 285 | 513.73 | 0.55476 | 5412 | ||
| Synonymous | 1.69 | 641 | 698 | 0.919 | 0.0000487 | 5106 |
| Loss of Function | 5.70 | 59 | 129 | 0.458 | 0.00000618 | 1478 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00063 | 0.00062 | rare |
| Latino/Admixed American | 0.00093 | 0.00093 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00050 | 0.00049 | rare |
| Finnish | 0.00038 | 0.00037 | rare |
| European (Non-Finnish) | 0.00096 | 0.00095 | rare |
| South Asian | 0.00045 | 0.00042 | rare |
| Other | 0.0012 | 0.0011 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Receptor for inositol 1,4,5-trisphosphate, a second messenger that mediates the release of intracellular calcium.;
Intolerance Scores
- LoFtool
- 0.0485
- RVIS EVS
- -4.09
- RVIS percentile EVS
- 0.17
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.862
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |