STIM1
protein-codingstromal interaction molecule 1, the group of MicroRNA protein coding host genes|Sterile alpha motif domain containing
Gene summary
This gene encodes a type 1 transmembrane protein that mediates Ca2+ influx after depletion of intracellular Ca2+ stores by gating of store-operated Ca2+ influx channels (SOCs). It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocrotical carcinoma, and lung, ovarian, and breast cancer. This gene may play a role in malignancies and disease that involve this region, as well as early hematopoiesis, by mediating attachment to stromal cells. Mutations in this gene are associated with fatal classic Kaposi sarcoma, immunodeficiency due to defects in store-operated calcium entry (SOCE) in fibroblasts, ectodermal dysplasia and tubular aggregate myopathy. This gene is oriented in a head-to-tail configuration with the ribonucleotide reductase 1 gene (RRM1), with the 3' end of this gene situated 1.6 kb from the 5' end of the RRM1 gene. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~238.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013008
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0024531
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0024531
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008051
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008497
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008051
Submitter: ClinGen
STIM1 was first reported in relation to autosomal dominant tubular aggregate myopathy in 2013 (Bohm et al., PMID: 23332920). Variants in this gene have also been reported in association with Stormorken Syndrome, York Platelet Syndrome, and an Immunodeficiency phenotype (PMIDs: 25577287, 24591628, 24619930). Stormorken and York Platelet have been evaluated by ClinGen Lumping and Splitting guidelines and determined to be the same entity as Tubular Aggregate Myopathy with a spectrum of phenotypic severity. At least 17 unique predominantly 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 24 probands in 10 publications (PMIDs: 23332920, 25326555, 25577287, 24591628, 24619930, 28624464, 27876257, 24570283, 25953320, 27066587). Variants in this gene segregated with disease in a number of additional family members, however no families were large enough to draw meaningful evidence. More genetic evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous gain of function, with alteration of particularly the EF-hand domain 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 several mouse and zebrafish models, biochemical function evidence, and functional studies. Each model recapitulates some amount of the phenotypes shown in humans including thrombocytopenia, muscle weakness, and muscle fiber atrophy. Additionally, STIM1's role in SOCE and the resulting always activated state when the expression and function of the protein is altered show clear correlations with the displayed phenotypes as both platelet function/clotting and skeletal muscle signalling relies on calcium flow. In summary, STIM1 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.
Inheritance Pattern: AD
Disease ID:MONDO:0024531
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013008
Submitter: ClinGen
STIM1 was first reported in relation to autosomal recessive combined immunodeficiency in 2009 (Picard et al., PMID: 19420366). Variants in STIM1 have been reported in individuals with the following disease entities: autosomal dominant tubular aggregate myopathy and autosomal recessive combined immunodeficiency. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern, and phenotypic variability between these disease entities. Therefore, the following disease entities have been split: tubular aggregate myopathy MONDO:0008051, combined immunodeficiency due to STIM1 deficiency MONDO:0013008. The split curation for autosomal dominant tubular aggregate myopathy has been curated separately. Combined immunodeficiency due to STIM1 deficiency is characterized by defective regulatory T cell activity. Clinical presentation is variable but often includes early-onset recurrent infections, autoimmunity, non-progressive myopathy, ectodermal dysplasia, iris hypoplasia, and developmental delay. Heterozygotes are not known to be clinically affected. Five variants including nonsense, frameshift, splice site, and gross deletion have been reported in five probands in five publications and are included in this curation (PMIDs: 19420366, 20876309, 33733462, 37898571, 38578569). Segregation with disease has been observed within families. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by functional and rescue assays (PMIDs: 19420366, 20876309). Patient cells show defective store-operated Ca2+ entry (SOCE), and expression of wild-type STIM1 restores SOCE. In summary, there is definitive evidence supporting the relationship between STIM1 and autosomal recessive combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID GCEP on the meeting date August 21, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0008497
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013008
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013008
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0024531
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013008
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Dental; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic; Renal
Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic
Rationale: In Stormorken syndrome, individuals may demonstrate hematologic anomalies including anemia, thrombocytopenia, and bleeding diathesis, and awareness may allow preventive measures and prompt treatment; Individuals have been described with cardiovascular anomalies (eg, intracranial aneurysms), and awareness may allow surveillance and early management; In Immunodeficiency 10, individuals may suffer early and severe (including fatal) infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals may have hematologic abnormalities, including autoimmune hemolytic anemia and thrombocytopenia, which have been reported as steroid-responsive; HSCT has been reported
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to STIM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001382567.1. 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 | 5 | 197 | 1 | 203 | ||
| missense | 8 | 11 | 438 | 18 | 3 | 478 |
| nonsense | 3 | 1 | 3 | 7 | ||
| start loss | 0 | |||||
| frameshift | 7 | 2 | 1 | 10 | ||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 5 | 11 | ||
| Total | 19 | 19 | 452 | 215 | 4 | 709 |
Highest pathogenic variant AF is 0.0000041042927
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001369496.1 | 13 | MANE Select | |
| Ensembl | ENSP00000433266.2 | 13 | MANE Select | |
| RefSeq | NP_001264890.1 | 12 | Standard | |
| RefSeq | NP_001264891.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Platelet activation - Homo sapiens (human)
- Calcium signaling pathway - Homo sapiens (human)
- Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
- Signaling by the B Cell Receptor (BCR)
- Immune System
Biological Process
- store-operated calcium entry
- detection of calcium ion
- cellular calcium ion homeostasis
- activation of store-operated calcium channel activity
- positive regulation of adenylate cyclase activity
Molecular Function
- protease binding
- calcium channel regulator activity
- calcium ion binding
- protein binding
- identical protein binding
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum membrane
- microtubule
- plasma membrane
- integral component of plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000300737
- Coding exons
- 12
- Length
- 238683
- Individuals with no LoFs
- 125739
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 9
- Defined
- 125748
- p
- 0.0000358
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.12 | 279 | 398 | 0.701 | 0.0000235 | 4532 |
| Missense (PolyPhen) | 69 | 119.06 | 0.57954 | 1386 | ||
| Synonymous | -0.363 | 158 | 152 | 1.04 | 0.00000831 | 1319 |
| Loss of Function | 4.19 | 6 | 31.3 | 0.192 | 0.00000173 | 351 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000069 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores (PubMed:15866891, PubMed:16005298, PubMed:16208375, PubMed:16537481, PubMed:16733527, PubMed:16766533, PubMed:16807233, PubMed:18854159, PubMed:19249086, PubMed:22464749, PubMed:24069340, PubMed:24351972, PubMed:24591628, PubMed:26322679, PubMed:25326555, PubMed:28219928). Acts as Ca(2+) sensor in the endoplasmic reticulum via its EF-hand domain. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates the Ca(2+) release-activated Ca(2+) (CRAC) channel subunit ORAI1 (PubMed:16208375, PubMed:16537481). Involved in enamel formation (PubMed:24621671). Activated following interaction with STIMATE, leading to promote STIM1 conformational switch (PubMed:26322679). {ECO:0000269|PubMed:15866891, ECO:0000269|PubMed:16005298, ECO:0000269|PubMed:16208375, ECO:0000269|PubMed:16537481, ECO:0000269|PubMed:16733527, ECO:0000269|PubMed:16766533, ECO:0000269|PubMed:16807233, ECO:0000269|PubMed:18854159, ECO:0000269|PubMed:19249086, ECO:0000269|PubMed:22464749, ECO:0000269|PubMed:24069340, ECO:0000269|PubMed:24351972, ECO:0000269|PubMed:24591628, ECO:0000269|PubMed:24621671, ECO:0000269|PubMed:25326555, ECO:0000269|PubMed:26322679, ECO:0000269|PubMed:28219928}.;
- Disease
- DISEASE: Immunodeficiency 10 (IMD10) [MIM:612783]: An immune disorder characterized by recurrent infections, impaired activation and proliferative response of T-cells, decreased T-cell production of cytokines, lymphadenopathy, and normal lymphocytes counts and serum immunoglobulin levels. Additional features include thrombocytopenia, autoimmune hemolytic anemia, myopathy, partial iris hypoplasia, hepatosplenomegaly and defective enamel dentition. {ECO:0000269|PubMed:19420366, ECO:0000269|PubMed:22190180}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, tubular aggregate, 1 (TAM1) [MIM:160565]: 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. They may occur in a variety of circumstances, including inherited myopathies, alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness. {ECO:0000269|PubMed:23332920, ECO:0000269|PubMed:24570283, ECO:0000269|PubMed:25326555, ECO:0000269|PubMed:25953320}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Stormorken syndrome (STRMK) [MIM:185070]: A rare autosomal dominant disease characterized by mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. {ECO:0000269|PubMed:24591628, ECO:0000269|PubMed:24619930, ECO:0000269|PubMed:25577287}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.167
Intolerance Scores
- LoFtool
- 0.269
- RVIS EVS
- -0.22
- RVIS percentile EVS
- 37.54
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.810
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |