ITPR1

inositol 1,4,5-trisphosphate receptor type 1, the group of Protein phosphatase 1 regulatory subunits|Inositol 1,4,5-triphosphate receptors

Basic information

Region (hg38): 3:4493344-4847506

Previous symbols: [ "SCA15", "SCA16", "SCA29" ]

Links

ENSG00000150995 ∙ NCBI:3708 ∙ OMIM:147265 ∙ HGNC:6180 ∙ Uniprot:Q14643 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spinocerebellar ataxia type 15/16 (Strong), mode of inheritance: AD
• spinocerebellar ataxia type 29 (Strong), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Definitive), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Definitive), mode of inheritance: AR
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AR
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AR
• aniridia-cerebellar ataxia-intellectual disability syndrome (Supportive), mode of inheritance: AD
• spinocerebellar ataxia type 15/16 (Supportive), mode of inheritance: AD
• spinocerebellar ataxia type 29 (Supportive), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AR
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Moderate), mode of inheritance: AR
• aniridia-cerebellar ataxia-intellectual disability syndrome (Strong), mode of inheritance: AD
• spinocerebellar ataxia type 29 (Strong), mode of inheritance: AD
• spinocerebellar ataxia type 15/16 (Strong), mode of inheritance: AD
• spinocerebellar ataxia type 29 (Definitive), mode of inheritance: AD
• aniridia-cerebellar ataxia-intellectual disability syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Gillespie syndrome; Spinocerebellar ataxia 15; Spinocerebellar ataxia 29	AD/AR	General	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	Neurologic; Ophthalmologic	11445634; 11723290; 12828938; 14981189; 17030759; 17558851; 17590087; 18579805; 17932120; 21555639; 21367767; 21827915; 22318346; 22986007; 27108797; 27108798

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ITPR1 gene.

• not provided (1288 variants)
• Autosomal dominant cerebellar ataxia (208 variants)
• not specified (112 variants)
• Inborn genetic diseases (85 variants)
• Spinocerebellar ataxia type 29 (46 variants)
• Gillespie syndrome (35 variants)
• Spinocerebellar ataxia type 15/16 (24 variants)
• ITPR1-related condition (7 variants)
• Spinocerebellar ataxia type 29;Spinocerebellar ataxia type 15/16;Gillespie syndrome (7 variants)
• Intellectual disability (6 variants)
• Gillespie syndrome;Spinocerebellar ataxia type 29;Spinocerebellar ataxia type 15/16 (4 variants)
• Spinocerebellar ataxia type 15/16;Spinocerebellar ataxia type 29;Gillespie syndrome (4 variants)
• ITPR1-related syndromic and non-syndromic hereditary ataxias (3 variants)
• Neurodevelopmental disorder (2 variants)
• See cases (2 variants)
• Gillespie syndrome;Spinocerebellar ataxia type 15/16;Spinocerebellar ataxia type 29 (2 variants)
• Bilateral congenital mydriasis (1 variants)
• Gillespie syndrome;Spinocerebellar ataxia type 15/16 (1 variants)
• Spinocerebellar ataxia type 29;Gillespie syndrome (1 variants)
• ITPR1-associated cerebellar ataxia spectrum disorder (1 variants)
• Spastic ataxia (1 variants)
• Atypical behavior;Progressive gait ataxia;Slurred speech;Movement disorder (1 variants)
• Anterior segment dysgenesis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ITPR1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			34	254	24	312
missense	10	26	495	13	2	546
nonsense	4	2				6
start loss			1			1
frameshift	2	2	1			5
inframe indel	1	1	4			6
splice donor/acceptor (+/-2bp)	3	4	2			9
splice region	1		44	41	6	92
non coding		1	37	210	193	441
Total	20	36	574	477	219

Highest pathogenic variant AF is 0.00000658

Variants in ITPR1

This is a list of pathogenic ClinVar variants found in the ITPR1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-4493356-C-T		Autosomal dominant cerebellar ataxia	Uncertain significance (Jan 13, 2018)
3-4493357-A-T		Autosomal dominant cerebellar ataxia	Benign (Jan 12, 2018)
3-4493383-C-T		Autosomal dominant cerebellar ataxia	Benign (Jan 13, 2018)
3-4493454-G-A		Autosomal dominant cerebellar ataxia	Benign (Jan 12, 2018)
3-4493540-C-G		Autosomal dominant cerebellar ataxia	Uncertain significance (Jan 13, 2018)
3-4493555-C-A		Autosomal dominant cerebellar ataxia	Uncertain significance (Jan 12, 2018)
3-4493595-C-T		Autosomal dominant cerebellar ataxia	Uncertain significance (Jan 12, 2018)
3-4494442-A-G		Autosomal dominant cerebellar ataxia	Benign (Jan 13, 2018)
3-4494460-C-T		Autosomal dominant cerebellar ataxia	Uncertain significance (Apr 27, 2017)
3-4516132-G-A			Likely benign (Oct 05, 2018)
3-4516141-A-G			Likely benign (Oct 05, 2018)
3-4516331-A-G			Benign (Jul 03, 2018)
3-4516359-A-G			Likely benign (Aug 14, 2018)
3-4516420-T-C			Benign (Jul 03, 2018)
3-4516490-A-G		Autosomal dominant cerebellar ataxia • not specified	Conflicting classifications of pathogenicity (Mar 17, 2023)
3-4516493-T-C			Uncertain significance (Oct 06, 2018)
3-4516511-G-A			Uncertain significance (Dec 03, 2022)
3-4516524-T-C			Likely benign (Sep 13, 2022)
3-4516539-T-A		Autosomal dominant cerebellar ataxia	Uncertain significance (Jan 13, 2018)
3-4516545-C-T			Likely benign (Jun 23, 2023)
3-4516546-G-A			Uncertain significance (Oct 02, 2022)
3-4516548-G-A		Autosomal dominant cerebellar ataxia • Spinocerebellar ataxia type 29;Spinocerebellar ataxia type 15/16;Gillespie syndrome • not specified	Benign (Jan 17, 2024)
3-4516556-C-T			Uncertain significance (Sep 22, 2022)
3-4516557-G-A		Autosomal dominant cerebellar ataxia • ITPR1-related disorder	Benign/Likely benign (Jan 22, 2024)
3-4516612-C-G			Benign (Aug 31, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ITPR1	protein_coding	protein_coding	ENST00000302640	59	354493

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.10e-14	124688	0	25	124713	0.000100

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.60	895	1.51e+3	0.594	0.0000871	18185
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000286	0.000281
Ashkenazi Jewish	0.000103	0.0000993
East Asian	0.000281	0.000278
Finnish	0.0000944	0.0000928
European (Non-Finnish)	0.0000801	0.0000796
Middle Eastern	0.000281	0.000278
South Asian	0.0000681	0.0000654
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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);Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human);Long-term potentiation - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Oocyte meiosis - Homo sapiens (human);Thyroid hormone synthesis - Homo sapiens (human);Long-term depression - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Huntington,s disease - Homo sapiens (human);Gap junction - Homo sapiens (human);Gastric acid secretion - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Glucagon signaling pathway - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Estrogen signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);C-type lectin receptor signaling pathway - Homo sapiens (human);Renin secretion - Homo sapiens (human);Salivary secretion - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Phosphatidylinositol signaling system - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Apoptosis - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Alzheimers Disease;Myometrial Relaxation and Contraction Pathways;G Protein Signaling Pathways;Cell-type Dependent Selectivity of CCK2R Signaling;Calcium Regulation in the Cardiac Cell;T-Cell antigen Receptor (TCR) Signaling Pathway;Serotonin HTR1 Group and FOS Pathway;Serotonin Receptor 2 and ELK-SRF-GATA4 signaling;Signaling by GPCR;Antigen activates B Cell Receptor (BCR) leading to generation of second messengers;Signaling by WNT;Signal Transduction;VEGFA-VEGFR2 Pathway;B cell receptor signaling;GPCR GroupI metabotropic glutamate receptor;Signaling by the B Cell Receptor (BCR);GPCR signaling-G alpha q;CLEC7A (Dectin-1) induces NFAT activation;CD4 T cell receptor signaling-ERK cascade;CLEC7A (Dectin-1) signaling;C-type lectin receptors (CLRs);Role of phospholipids in phagocytosis;Fcgamma receptor (FCGR) dependent phagocytosis;FCERI mediated Ca+2 mobilization;Fc epsilon receptor (FCERI) signaling;TCR;Innate Immune System;Immune System;Metabolism;Adaptive Immune System;Ion homeostasis;Regulation of insulin secretion;BCR;Effects of PIP2 hydrolysis;Cardiac conduction;Muscle contraction;Platelet activation, signaling and aggregation;Ca2+ pathway;Beta-catenin independent WNT signaling;Hemostasis;DAG and IP3 signaling;Signaling by VEGF;PLC beta mediated events;G-protein mediated events;Opioid Signalling;G alpha (i) signalling events;Signaling by Receptor Tyrosine Kinases;Integration of energy metabolism;cGMP effects;Nitric oxide stimulates guanylate cyclase;Elevation of cytosolic Ca2+ levels;Platelet calcium homeostasis;VEGF;Platelet homeostasis;G alpha (q) signalling events;GPCR downstream signalling;Intracellular signaling by second messengers;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling-NFkB cascade;VEGFR2 mediated cell proliferation;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.454

Intolerance Scores

• loftool: 0.0141
• rvis_EVS: -3.35
• rvis_percentile_EVS: 0.4

Haploinsufficiency Scores

• pHI: 0.490
• hipred: Y
• hipred_score: 0.639
• ghis: 0.580

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.932

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Itpr1
• Phenotype: embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; cellular phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: response to hypoxia;calcium ion transport;signal transduction;post-embryonic development;regulation of autophagy;platelet activation;endoplasmic reticulum calcium ion homeostasis;epithelial fluid transport;inositol phosphate-mediated signaling;regulation of insulin secretion;negative regulation of calcium-mediated signaling;voluntary musculoskeletal movement;release of sequestered calcium ion into cytosol;intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress;regulation of postsynaptic cytosolic calcium ion concentration;regulation of cardiac conduction
• Cellular component: nuclear inner membrane;nucleolus;endoplasmic reticulum;endoplasmic reticulum membrane;plasma membrane;calcineurin complex;postsynaptic density;membrane;integral component of membrane;sarcoplasmic reticulum;transport vesicle membrane;cytoplasmic vesicle membrane;secretory granule membrane;platelet dense granule membrane;platelet dense tubular network;platelet dense tubular network membrane;perinuclear region of cytoplasm;Schaffer collateral - CA1 synapse
• 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;calcium channel inhibitor activity;phosphatidylinositol binding;inositol 1,4,5 trisphosphate binding;inositol 1,4,5-trisphosphate receptor activity involved in regulation of postsynaptic cytosolic calcium levels