GeneBe

ORAI1

protein-coding

ORAI calcium release-activated calcium modulator 1, the group of ORAI calcium release-activated calcium modulators

Gene summary

The protein encoded by this gene is a membrane calcium channel subunit that is activated by the calcium sensor STIM1 when calcium stores are depleted. This type of channel is the primary way for calcium influx into T-cells. Defects in this gene are a cause of immune dysfunction with T-cell inactivation due to calcium entry defect type 1 (IDTICED1). [provided by RefSeq, Sep 2011]

Previous symbols:
  • TMEM142A

MANE transcript

N/A

Inheritance

AD, AR

ClinVar variants

P:15U:207B:114

Top phenotype

Immunodeficiency 9

Max pathogenic AF

—

Genomic locus

chr12:121,626,509-121,643,218

External References & Databases

Ensembl (ENSG00000276045)NCBI Gene (84876)OMIM (610277)HGNC:25896GenCCUniProt (Q96D31)AlphaFoldClinVar (ORAI1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~16.7 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Stormorken syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008497

Submitter: Orphanet

tubular aggregate myopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008051

Submitter: Orphanet

tubular aggregate myopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008051

Submitter: PanelApp Australia

combined immunodeficiency due to ORAI1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013007

Submitter: Orphanet

combined immunodeficiency due to ORAI1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013007

Submitter: Labcorp Genetics (formerly Invitae)

tubular aggregate myopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008051

Submitter: ClinGen

ORAI1 was first reported in relation to autosomal dominant tubular aggregate myopathy in 2014 (Nesin et al., PMID: 24591628). Variants in this gene have also been reported in association with an Immunodeficiency phenotype, which will be assessed separately. At least 6 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 8 probands in 4 publications (PMIDs: 24591628, 25227914, 27882542, 28058752). Variants in this gene segregated with disease in a significant number of additional family members via whole exome sequencing. A significant amount of variant-level evidence was available, with each individual variant demonstrating altered SOCE activation and Ca2+ homeostasis. The mechanism for disease is heterozygous gain of function, with alteration of several domains responsible for altered calcium signalling detection and resulting consitutive activation of store-operated calcium entry regardless of the intracellular calcium levels. (Morin et al. 2019, PMID: 31448844) This gene-disease association and mechanism is supported by biochemical function evidence, expression evidence, physical interaction with STIM1, and functional studies demonstrating SOCE loss and rescue via ORAI1 expression. ORAI1's role in SOCE, relationship with STIM1, and the resulting always activated state when the expression and function of the protein is altered show clear correlations with the displayed phenotypes as skeletal muscle signalling relies on calcium flow. Currently there are no available models that properly demonstrate TAM phenotypes, likely due to the necessity of a knock-in model and less research performed than on STIM1. In summary, ORAI1 is definitively associated with autosomal dominant tubular aggregate myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

myopathy, tubular aggregate, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014383

Submitter: Labcorp Genetics (formerly Invitae)

combined immunodeficiency due to ORAI1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013007

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Immunodeficiency 9AR

Manifestation: Allergy/Immunology/Infectious; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis; early and aggressive treatment of infections

Refs: 8814256; 15452313; 16582901; 21873530; 24591628; 25227914Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ORAI1 variants in ClinVar

4 Conditions Cataloged
Myopathy, tubular aggregate, 2Total: 2
Myopathy, tubular aggregate, 2;Combined immunodeficiency due to ORAI1 deficiencyTotal: 2
Combined immunodeficiency due to ORAI1 deficiencyTotal: 2
Myopathy with tubular aggregatesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript . 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.

EffectPLPVUSLBBSum
synonymous
10
clinvar
97
clinvar
6
clinvar
 113
missense
3
clinvar
1
clinvar
178
clinvar
6
clinvar
1
clinvar
 189
nonsense
2
clinvar
3
clinvar
 5
start loss
1
clinvar
 1
frameshift
3
clinvar
6
clinvar
14
clinvar
3
clinvar
1
clinvar
 27
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total692071068336
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 1 of 1 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
ENST00000617316.2EnsemblENSP00000482568.23Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
orai1bDanio rerio

Structure: cardiac muscle cell

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Primary immunodeficiency - Homo sapiens (human)
  • Platelet activation - Homo sapiens (human)
  • Cortisol synthesis and secretion - Homo sapiens (human)
  • Aldosterone synthesis and secretion - Homo sapiens (human)
  • Cushing,s syndrome - Homo sapiens (human)

Biological Process

  • store-operated calcium entry
  • adaptive immune response
  • positive regulation of adenylate cyclase activity
  • regulation of calcium ion transport
  • positive regulation of calcium ion transport

Molecular Function

  • protein binding
  • calmodulin binding
  • store-operated calcium channel activity
  • identical protein binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • membrane
  • basolateral plasma membrane
  • protein-containing complex

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Ca(2+) release-activated Ca(2+) (CRAC) channel subunit which mediates Ca(2+) influx following depletion of intracellular Ca(2+) stores and channel activation by the Ca(2+) sensor, STIM1 (PubMed:16582901, PubMed:16645049, PubMed:16733527, PubMed:16766533, PubMed:16807233, PubMed:19249086, PubMed:23307288, PubMed:24351972, PubMed:24591628, PubMed:28219928). CRAC channels are the main pathway for Ca(2+) influx in T-cells and promote the immune response to pathogens by activating the transcription factor NFAT (PubMed:16582901). {ECO:0000269|PubMed:16582901, ECO:0000269|PubMed:16645049, ECO:0000269|PubMed:16733527, ECO:0000269|PubMed:16766533, ECO:0000269|PubMed:16807233, ECO:0000269|PubMed:19249086, ECO:0000269|PubMed:23307288, ECO:0000269|PubMed:24351972, ECO:0000269|PubMed:24591628, ECO:0000269|PubMed:28219928}.;
Disease
DISEASE: Immunodeficiency 9 (IMD9) [MIM:612782]: An immune disorder characterized by recurrent infections, impaired activation and proliferative response of T-cells, decreased T-cell production of cytokines, and normal lymphocytes counts and serum immunoglobulin levels. In surviving patients ectodermal dysplasia with anhidrosis and non-progressive myopathy may be observed. {ECO:0000269|PubMed:16147976, ECO:0000269|PubMed:16582901}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, tubular aggregate, 2 (TAM2) [MIM:615883]: A rare congenital myopathy characterized by regular arrays of membrane tubules on muscle biopsies without additional histopathological hallmarks. Tubular aggregates in muscle are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. TAM2 patients have myopathy and pupillary abnormalities. {ECO:0000269|PubMed:24591628, ECO:0000269|PubMed:28058752}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.141

Intolerance Scores

LoFtool
0.486
RVIS EVS
0.1
RVIS percentile EVS
61.49

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.542

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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