STIM1

Chr 11ARAD

stromal interaction molecule 1

Also known as: D11S4896E, GOK, IMD10, STRMK, TAM, TAM1

NCBI Gene: 6786 ENSG00000167323 UniProt: Q13586 OMIM: 605921

The STIM1 protein acts as a calcium sensor that gates major calcium channels at the plasma membrane and mediates store-operated calcium entry following depletion of intracellular calcium stores. Mutations cause immunodeficiency 10, tubular aggregate myopathy, and Stormorken syndrome, with both autosomal recessive and autosomal dominant inheritance patterns reported. The gene is highly constrained (LOEUF 0.378), and the associated conditions affect multiple systems including immune function, muscle, and ectodermal structures.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

GOFmechanismAR/ADLOEUF 0.383 OMIM phenotypes

Clinical Summary— STIM1

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Gene-Disease Validity (ClinGen)

tubular aggregate myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.78) — some intolerance to loss-of-function variants.

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ClinVar Variants

40 unique Pathogenic / Likely Pathogenic· 486 VUS of 922 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — STIM1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.775

Z-score 4.19

OE 0.19 (0.10–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.12Z-score

OE missense 0.70 (0.64–0.77)

279 obs / 397.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.10–0.38)

0≤0.351.4

Missense OE?0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 6 / 31.3Missense obs/exp: 279 / 397.9Syn Z: -0.36

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSTIM1-related tubular-aggregate myopathyGOFAD

This gene — mechanism propensity

0.5869th %ile

GOF

0.6834th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 50% of P/LP variants are LoF · LOEUF 0.38

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFBy contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York1

LOFTaken together, the hearts of STIM1 haploinsufficient mice had a superficial resemblance to the WT phenotype under stress-free conditions; however, STIM1 haploinsufficient mice showed a maladaptive response to cardiac pressure overload.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

922 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22

Likely Pathogenic18

VUS486

Likely Benign323

Benign43

Conflicting20

Pathogenic

Likely Pathogenic

486

VUS

323

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	8	3	0	22
Likely Pathogenic	9	8	1	0	18
VUS	9	438	33	6	486
Likely Benign	3	32	110	178	323
Benign	0	5	35	3	43
Conflicting	—				20
Total	32	491	182	187	912

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

21 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap STIM1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →