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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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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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 OE0.19 (0.10–0.38)

0≤0.351.4

Missense OE0.70 (0.64–0.77)

0≤0.61.4

Synonymous OE1.04

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

0.5869th %ile

GOF

0.6834th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOF1 literature citation · LOEUF 0.38

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 YorkPMID:26469693

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.PMID:29145451

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