Stormorken syndrome

Summary

Stormorken syndrome (MONDO:0008497) is a disease caused by STIM1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: STIM1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 781
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000348	High forehead	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000616	Miosis	Very frequent (80-99%)
HP:0000979	Purpura	Very frequent (80-99%)
HP:0001746	Asplenia	Very frequent (80-99%)
HP:0001872	Abnormality of thrombocytes	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0003011	Abnormality of the musculature	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0008064	Ichthyosis	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0001928	Abnormality of coagulation	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Stormorken syndrome
Mondo ID	MONDO:0008497
MeSH	C566108
OMIM	185070
Orphanet	3204
DOID	DOID:0060354
SNOMED CT	711407000
UMLS	C1861451
MedGen	350028
GARD	0005188
Is cancer (heuristic)	no

Also known as: Stormorken syndrome · STRMK · Thrombocytopathy asplenia miosis · Thrombocytopathy-asplenia-miosis syndrome

Data availability: 781 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytopenia › inherited thrombocytopenia › syndromic constitutional thrombocytopenia › Stormorken syndrome

Related subtypes (11): Jacobsen syndrome, platelet storage pool deficiency, thrombocytopenia-absent radius syndrome, radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome, GNE myopathy, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, thrombocytopenia 6, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, marcothrombocytopenia with mitral valve insufficiency, DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome, ACTB-associated syndromic thrombocytopenia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

298 uncertain significance, 246 likely benign, 12 benign, 12 pathogenic, 10 likely pathogenic, 10 benign/likely benign, 8 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
132887	NM_001382567.1(STIM1):c.910C>T (p.Arg304Trp)	STIM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1365102	NM_001382567.1(STIM1):c.869_887del (p.Ile290fs)	STIM1	Pathogenic	criteria provided, single submitter
1371047	NC_000011.9:g.(?3988762)(4113028_?)del	STIM1	Pathogenic	criteria provided, single submitter
1395833	NM_001382567.1(STIM1):c.262A>G (p.Ser88Gly)	STIM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143191	NM_001382567.1(STIM1):c.343A>T (p.Ile115Phe)	STIM1	Pathogenic	criteria provided, single submitter
1452705	NM_001382567.1(STIM1):c.163_164del (p.Leu55fs)	STIM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457776	NM_001382567.1(STIM1):c.1189del (p.Ala397fs)	STIM1	Pathogenic	criteria provided, single submitter
1459002	NC_000011.9:g.(?4076736)(4076887_?)del	STIM1	Pathogenic	criteria provided, single submitter
2928208	NM_001382567.1(STIM1):c.1463T>A (p.Leu488Ter)	STIM1	Pathogenic	criteria provided, single submitter
3752806	NM_001382567.1(STIM1):c.757C>T (p.Arg253Ter)	STIM1	Pathogenic	criteria provided, single submitter
3755531	NM_001382567.1(STIM1):c.30G>A (p.Trp10Ter)	STIM1	Pathogenic	criteria provided, single submitter
3756856	NM_001382567.1(STIM1):c.1437_1444dup (p.Glu482fs)	STIM1	Pathogenic	criteria provided, single submitter
3763455	NM_001382567.1(STIM1):c.325C>T (p.His109Tyr)	STIM1	Pathogenic	criteria provided, single submitter
41464	NM_001382567.1(STIM1):c.1285C>T (p.Arg429Cys)	STIM1	Pathogenic	criteria provided, single submitter
41483	NM_001382567.1(STIM1):c.326A>G (p.His109Arg)	STIM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4532276	NM_001382567.1(STIM1):c.148C>T (p.Arg50Ter)	STIM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1476711	NM_001382567.1(STIM1):c.386-1G>A	STIM1	Likely pathogenic	criteria provided, single submitter
1703798	NM_001382567.1(STIM1):c.563A>G (p.Gln188Arg)	STIM1	Likely pathogenic	criteria provided, single submitter
189363	NM_001382567.1(STIM1):c.239A>C (p.Asn80Thr)	STIM1	Likely pathogenic	criteria provided, single submitter
2020521	NM_001382567.1(STIM1):c.270+2T>C	STIM1	Likely pathogenic	criteria provided, single submitter
2090235	NM_001382567.1(STIM1):c.1568-1G>T	STIM1	Likely pathogenic	criteria provided, single submitter
2091216	NM_001382567.1(STIM1):c.792-1G>A	STIM1	Likely pathogenic	criteria provided, single submitter
2424636	NC_000011.9:g.(?4045083)(4045237_?)dup	STIM1	Likely pathogenic	criteria provided, single submitter
2506361	NM_001382567.1(STIM1):c.251A>C (p.Asp84Ala)	STIM1	Likely pathogenic	criteria provided, single submitter
3759326	NM_001382567.1(STIM1):c.270+1_270+2insCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAAGTGATGAGG	STIM1	Likely pathogenic	criteria provided, single submitter
4785692	NM_001382567.1(STIM1):c.270+1G>C	STIM1	Likely pathogenic	criteria provided, single submitter
258976	NM_001382567.1(STIM1):c.2021G>A (p.Arg674His)	LOC124418421	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2183056	NM_001382567.1(STIM1):c.1715G>A (p.Ser572Asn)	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235347	NM_001382567.1(STIM1):c.1664C>T (p.Ser555Phe)	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2933355	NM_001382567.1(STIM1):c.140-5C>T	STIM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
STIM1	Strong	Autosomal dominant	Stormorken syndrome	11
ORAI1	Supportive	Autosomal dominant	Stormorken syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STIM1	Orphanet:2593	Tubular aggregate myopathy
STIM1	Orphanet:317430	Combined immunodeficiency due to STIM1 deficiency
STIM1	Orphanet:3204	Stormorken-Sjaastad-Langslet syndrome
ORAI1	Orphanet:2593	Tubular aggregate myopathy
ORAI1	Orphanet:317428	Combined immunodeficiency due to ORAI1 deficiency
ORAI1	Orphanet:3204	Stormorken-Sjaastad-Langslet syndrome
PGAP2	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STIM1	HGNC:11386	ENSG00000167323	Q13586	Stromal interaction molecule 1	gencc,clinvar
ORAI1	HGNC:25896	ENSG00000276045	Q96D31	Calcium release-activated calcium channel protein 1	gencc
PGAP2	HGNC:17893	ENSG00000148985	Q9UHJ9	Acyltransferase PGAP2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STIM1	Stromal interaction molecule 1	Acts as a Ca(2+) sensor that gates two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.
ORAI1	Calcium release-activated calcium channel protein 1	Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.
PGAP2	Acyltransferase PGAP2	Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STIM1	Other/Unknown	no		SAM, SAM/pointed_sf, SOAR_STIM1/2
ORAI1	Other/Unknown	no		CRAC_channel, Orai_sf
PGAP2	Other/Unknown	no		CWH43_N, PGAP2

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
gastrocnemius	1
muscle of leg	1
granulocyte	1
skin of leg	1
corpus epididymis	1
lower esophagus mucosa	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STIM1	237	ubiquitous	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
ORAI1	177	ubiquitous	yes	granulocyte, hindlimb stylopod muscle, skin of leg
PGAP2	280	ubiquitous	marker	corpus epididymis, lower esophagus mucosa, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STIM1	3,074
ORAI1	1,239
PGAP2	887

Intra-cohort edges

A	B	Sources
ORAI1	STIM1	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STIM1	Q13586	6
ORAI1	Q96D31	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP2	Q9UHJ9	90.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Elevation of cytosolic Ca2+ levels	2	713.8×	2e-05	STIM1, ORAI1
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	2	356.9×	4e-05	STIM1, ORAI1
Ion homeostasis	2	203.9×	9e-05	STIM1, ORAI1
Platelet calcium homeostasis	1	356.9×	0.008	STIM1
Signaling by the B Cell Receptor (BCR)	1	173.0×	0.013	STIM1
Platelet homeostasis	1	139.3×	0.013	STIM1
Cardiac conduction	1	54.4×	0.029	STIM1
Muscle contraction	1	38.6×	0.035	STIM1
Hemostasis	1	18.0×	0.067	STIM1
Adaptive Immune System	1	14.9×	0.073	STIM1
Immune System	1	6.5×	0.148	STIM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of adenylate cyclase activity	2	2246.9×	4e-06	STIM1, ORAI1
store-operated calcium entry	2	1123.5×	1e-05	STIM1, ORAI1
regulation of calcium ion transport	2	535.0×	3e-05	STIM1, ORAI1
activation of store-operated calcium channel activity	1	1123.5×	0.004	STIM1
mammary gland epithelium development	1	624.1×	0.005	ORAI1
ligand-gated ion channel signaling pathway	1	624.1×	0.005	ORAI1
enamel mineralization	1	401.2×	0.006	STIM1
detection of calcium ion	1	374.5×	0.006	STIM1
regulation of store-operated calcium entry	1	351.1×	0.006	STIM1
calcium-ion regulated exocytosis	1	330.4×	0.006	ORAI1
calcineurin-NFAT signaling cascade	1	280.9×	0.006	ORAI1
calcium ion import	1	267.5×	0.006	ORAI1
positive regulation of calcium ion transport	1	193.7×	0.008	ORAI1
GPI anchor biosynthetic process	1	165.2×	0.009	PGAP2
positive regulation of insulin secretion	1	85.1×	0.016	ORAI1
calcium ion transmembrane transport	1	70.2×	0.018	ORAI1
intracellular calcium ion homeostasis	1	48.4×	0.024	STIM1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	43.9×	0.025	ORAI1
positive regulation of angiogenesis	1	38.5×	0.027	STIM1
adaptive immune response	1	28.1×	0.035	ORAI1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
STIM1	TERIFLUNOMIDE
ORAI1	MIBEFRADIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ORAI1	5	4
STIM1	2	4
PGAP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TERIFLUNOMIDE	4	ORAI1, STIM1
MIBEFRADIL	4	ORAI1
ECONAZOLE	4	ORAI1
MICONAZOLE	4	ORAI1
ZEGOCRACTIN	2	ORAI1, STIM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ORAI1	59	Binding:57, Functional:1, ADMET:1
STIM1	35	Binding:33, Functional:1, ADMET:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

5 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TERIFLUNOMIDE	4	ORAI1, STIM1
MIBEFRADIL	4	ORAI1
ECONAZOLE	4	ORAI1
MICONAZOLE	4	ORAI1
ZEGOCRACTIN	2	ORAI1, STIM1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	STIM1, ORAI1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PGAP2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PGAP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.