ITPR1
protein-codinginositol 1,4,5-trisphosphate receptor type 1, the group of Protein phosphatase 1 regulatory subunits|Inositol 1,4,5-triphosphate receptors
Gene summary
This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]
- SCA15
- SCA16
- SCA29
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~354.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008795
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008795
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008795
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011694
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008795
Submitter: ClinGen
*ITPR1* encodes a calcium channel that releases calcium from the endoplasmic reticulum upon stimulation by inositol 1,4,5-trisphosphate (IP3). *ITPR1* was first reported in relation to both autosomal dominant and recessive Gillespie syndrome (also known as aniridia-cerebellar ataxia-intellectual disability syndrome) in 2016 (Gerber et al., PMID: 27108797; McEntagart et al., PMID: 27108798). Clinical features include aniridia or iris hypoplasia, hypotonia, non-progressive cerebellar ataxia, cerebellar atrophy, and variable intellectual disability. Affected individuals are usually diagnosed within the first year of life. The syndrome is caused by heterozygous dominant-negative missense variants or biallelic truncating variants in *ITPR1*. Based on the ClinGen Lumping and Splitting guidance, there are differences in inheritance pattern and molecular mechanism and therefore, the autosomal dominant and recessive forms of Gillespie syndrome were assessed separately. This curation concerns autosomal recessive Gillespie syndrome. Variants in *ITPR1* have also been implicated in two types of autosomal dominant spinocerebellar ataxia (SCA), in which iris development is normal: infantile-onset SCA29 and adult-onset SCA15. The relationship between *ITPR1* and spinocerebellar ataxia will be curated separately. Six homozygous or compound heterozygous truncating variants (nonsense, frameshift, and splice) that have been reported in five probands in three publications (PMIDs: 27108797, 29169895, 29663667) are included in this curation. The mechanism of pathogenicity appears to be partial loss of function. The recessive alleles are predicted to generate premature termination codons that appear to act as partial rather than full loss-of-function variants, possibly via exon skipping mechanisms (PMID: 27108797). *ITPR1* haploinsufficiency causes adult-onset SCA15; because carrier parents of individuals with recessive Gillespie syndrome are unaffected, there is no apparent haploinsufficient effect associated with these hypomorphic alleles. A single homozygous missense variant, located in the C-terminal channel domain, has been reported in a girl with features of Gillespie syndrome (PMID: 35574166); in the absence of functional evidence of pathogenicity, the significance of this variant is unclear. This gene-disease relationship is also supported by mouse models partially recapitulating the human phenotype (PMIDs: 8538767, 34338282). In summary, there is definitive evidence supporting the relationship between *ITPR1* and autosomal recessive Gillespie syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 23, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0007298
Submitter: ClinGen
*ITPR1* encodes a calcium channel that releases calcium from the endoplasmic reticulum upon stimulation by inositol 1,4,5-trisphosphate (IP3) and is enriched in the brain, particularly in the Purkinje cells of the cerebellum. *ITPR1* was first reported in relation to autosomal dominant spinocerebellar ataxia type 29 (SCA29) in 2012 (Huang et al., PMID: 22986007). Clinical features include cerebellar ataxia with onset in infancy or childhood, hypotonia, gross motor delay, oculomotor abnormalities, dysarthria, mild-to-moderate intellectual disability or learning disability, and cerebellar atrophy/hypoplasia. *ITPR1* has also been reported in relation to autosomal dominant spinocerebellar ataxia type 15 (SCA15), an adult-onset, slowly progressive cerebellar ataxia. Heterozygous missense variants cause SCA29, while heterozygous loss-of-function variants, mainly deletions, cause SCA15. Based on the ClinGen Lumping and Splitting guidance, there are differences in molecular mechanism and phenotype and therefore, the two types of spinocerebellar ataxia were assessed separately. This curation concerns autosomal dominant SCA29. The relationship between *ITPR1* and SCA15 will be curated separately by another gene curation expert panel. This curation includes 9 missense variants that have been reported in 10 probands in 6 publications (PMIDs: 25794864, 27062503, 28620721, 29925855, 31632679), and segregation data in one large family (PMID: 22986007). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The variants are often *de novo* but may also be inherited from an affected parent, and many are recurrent. Most reported variants cluster in the N-terminal IP3 binding domain, the C-terminal channel domain and the CAR8-binding region (PMID: 37964426). SCA29 variants within or near the IP3-binding domain of IP3R1 (including hotspot variants p.Thr267Met and p.Arg269Trp) abolish IP3-induced Ca2+ channel activity and several also reduce IP3 binding, suggesting that the mechanism of pathogenicity is dominant-negative loss of function (PMID: 30429331). However, the SCA29 variant p.Arg36Cys, located in the suppressor domain, and two variants in the CAR8-binding region (p.Ser1502Asp and p.Val1562Met), exhibit increased IP3 binding and elevation of intracellular Ca2+ signal compared to wild-type ITPR1 (PMIDs: 28620721, 30429331), indicating that both gain and loss of function can lead to SCA29. Of note, autosomal dominant and recessive forms of Gillespie syndrome, characterized by aniridia, cerebellar ataxia and intellectual disability, have been reported in relation to heterozygous missense variants in the C-terminal domain of ITPR1 or biallelic truncating variants, respectively. The relationship between *ITPR1* and Gillespie syndrome was evaluated separately. No obvious genotype-phenotype correlations have been observed for the SCA29 and Gillespie syndrome variants clustered in the C-terminal domain (PMID: 37964426). This gene-disease relationship is also supported by experimental evidence showing that ITPR1 interacts with CA8, an ITPR1-regulating protein implicated in spinocerebellar ataxia. Mice heterozygous for *Itpr1* null variants exhibit mild coordination deficits (PMID: 11334652), but do not replicate the ataxia phenotype observed in affected individuals with SCA29 missense variants (PMIDs: 8538767). In summary, there is definitive evidence supporting the relationship between *ITPR1* and autosomal dominant spinocerebellar ataxia type 29. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2021 and classified as Definitive. It was reevaluated on January 23, 2025 (SOP Version 11). Although additional evidence was curated, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0007298
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008795
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007298
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0008795
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0008795
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008795
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008795
Submitter: ClinGen
*ITPR1* encodes a calcium channel that releases calcium from the endoplasmic reticulum upon stimulation by inositol 1,4,5-trisphosphate (IP3). *ITPR1* was first reported in relation to both autosomal dominant and recessive Gillespie syndrome (also known as aniridia-cerebellar ataxia-intellectual disability syndrome) in 2016 (Gerber et al., PMID: 27108797; McEntagart et al., PMID: 27108798). Clinical features include aniridia or iris hypoplasia, hypotonia, non-progressive cerebellar ataxia, cerebellar atrophy, and variable intellectual disability. Affected individuals are usually diagnosed within the first year of life. The syndrome is caused by heterozygous dominant-negative missense variants or biallelic truncating variants in *ITPR1* that appear to act as partial rather than full loss-of-function variants (PMID: 27108797). Based on the ClinGen Lumping and Splitting guidance, there are differences in inheritance pattern and molecular mechanism and therefore, the autosomal dominant and recessive forms of Gillespie syndrome were assessed separately. This curation concerns autosomal dominant Gillespie syndrome. Seven unique heterozygous *ITPR1* variants (6 missense and 1 in-frame deletion) identified in 12 unrelated individuals in four publications (PMIDs: 27108797, 27108798, 28698159, 31340402) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The variants are often *de novo* but may also be inherited from an affected parent. All the missense or in-frame deletion variants in autosomal dominant Gillespie syndrome reported so far are located in the C-terminal region of ITPR1, mainly in the transmembrane channel domain, and affect a restricted number of residues (PMID: 37964426). The mechanism of pathogenicity appears to be dominant negative (PMIDs: 27108797, 27108798). Mice heterozygous for *Itpr1* null variants exhibit mild coordination deficits (PMID: 11334652), but do not replicate the ataxia or eye phenotype seen in Gillespie syndrome (PMIDs: 8538767, 27108798). Of note, variants in *ITPR1* have also been implicated in two types of autosomal dominant spinocerebellar ataxia, in which iris development is normal: infantile-onset spinocerebellar ataxia type 29, caused by heterozygous missense variants in *ITPR1*, and adult-onset spinocerebellar ataxia type 15, caused by heterozygous loss-of-function variants. The relationship between *ITPR1* and spinocerebellar ataxia will be curated separately. No obvious genotype-phenotype correlations have been observed for the Gillespie syndrome and spinocerebellar ataxia type 29 variants clustered in the C-terminal domain (PMID: 37964426). In summary, there is definitive evidence supporting the relationship between *ITPR1* and autosomal dominant Gillespie syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2021 and classified as Definitive. It was reevaluated on January 23, 2025 (SOP Version 11). Although additional evidence was curated, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0007298
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011694
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008795
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0008795
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011694
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008795
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007298
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic; Ophthalmologic
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 ITPR1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001378452.1. 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 | 35 | 472 | 12 | 519 | ||
| missense | 16 | 56 | 946 | 44 | 1 | 1063 |
| nonsense | 12 | 2 | 7 | 21 | ||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 5 | 3 | 11 | ||
| splice donor/acceptor (+/-2bp) | 3 | 9 | 13 | 25 | ||
| Total | 34 | 72 | 1005 | 516 | 13 | 1640 |
Highest pathogenic variant AF is 0.00024867817
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001365381.1 | 60 | MANE Select | |
| Ensembl | ENSP00000497605.1 | 60 | MANE Select | |
| RefSeq | NP_001093422.2 | 57 | Standard | |
| RefSeq | NP_001161744.1 | 59 | 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)
- 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
- response to hypoxia
- calcium ion transport
- signal transduction
- post-embryonic development
- regulation of autophagy
Molecular Function
- inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity
- calcium ion binding
- protein binding
- calcium ion transmembrane transporter activity
- calcium-release channel activity
Cellular Component
- nuclear inner membrane
- nucleolus
- endoplasmic reticulum
- endoplasmic reticulum membrane
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000302640
- Coding exons
- 59
- Length
- 354493
- Individuals with no LoFs
- 124688
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 25
- Defined
- 124713
- p
- 0.000100
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 5.60 | 895 | 1.51e+3 | 0.594 | 0.0000871 | 18185 |
| Missense (PolyPhen) | 297 | 762.12 | 0.3897 | 9627 | ||
| Synonymous | -1.71 | 657 | 604 | 1.09 | 0.0000384 | 5116 |
| Loss of Function | 9.93 | 11 | 136 | 0.0809 | 0.00000716 | 1665 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00020 | 0.00019 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00028 | 0.00028 | rare |
| Finnish | 0.000094 | 0.000093 | rare |
| European (Non-Finnish) | 0.000080 | 0.000080 | rare |
| South Asian | 0.000068 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Intracellular channel that mediates calcium release from the endoplasmic reticulum following stimulation by inositol 1,4,5- trisphosphate (PubMed:27108797). Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1 (By similarity). Plays a role in ER stress-induced apoptosis. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CaM kinase II, eventually leading to the activation of downstream apoptosis pathways (By similarity). {ECO:0000250|UniProtKB:P11881, ECO:0000269|PubMed:27108797}.;
- Disease
- DISEASE: Spinocerebellar ataxia 15 (SCA15) [MIM:606658]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA15 is an autosomal dominant cerebellar ataxia (ADCA). It is very slow progressing form with a wide range of onset, ranging from childhood to adult. Most patients remain ambulatory. {ECO:0000269|PubMed:17590087, ECO:0000269|PubMed:18579805}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia 29 (SCA29) [MIM:117360]: An autosomal dominant, congenital spinocerebellar ataxia characterized by early motor delay, hypotonia and mild cognitive delay. Affected individuals develop a very slowly progressive or non-progressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor. {ECO:0000269|PubMed:22986007, ECO:0000269|PubMed:26770814}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Gillespie syndrome (GLSP) [MIM:206700]: A rare disease characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, progressive cerebellar atrophy, and mental retardation. {ECO:0000269|PubMed:27108797, ECO:0000269|PubMed:27108798}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.454
Intolerance Scores
- LoFtool
- 0.0141
- RVIS EVS
- -3.35
- RVIS percentile EVS
- 0.4
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.932
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |