short QT syndrome type 1

Summary

short QT syndrome type 1 (MONDO:0012312) is a disease caused by KCNH2 (GenCC Definitive), with 3 cohort genes. The dominant Reactome pathway is Potassium Channels (3 cohort genes).

At a glance

• Causal gene: KCNH2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 180

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short QT syndrome type 1
Mondo ID	MONDO:0012312
MeSH	C566506
OMIM	609620
UMLS	C1865020
MedGen	355891
GARD	0018633
Is cancer (heuristic)	no

Also known as: KCNH2 short QT syndrome · short QT syndrome 1 · short QT syndrome caused by mutation in KCNH2 · short QT syndrome type 1 · SQT1 · SQTS

Data availability: 180 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › short QT syndrome › short QT syndrome type 1

Related subtypes (3): short QT syndrome type 2, short QT syndrome type 3, short QT syndrome 7

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

180 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 43 conflicting classifications of pathogenicity, 11 benign/likely benign, 10 pathogenic, 7 pathogenic/likely pathogenic, 5 likely benign, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14420	NM_000238.4(KCNH2):c.1682C>T (p.Ala561Val)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14427	NM_000238.4(KCNH2):c.1882G>A (p.Gly628Ser)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
14437	NM_000238.4(KCNH2):c.1764C>A (p.Asn588Lys)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675096	NM_000238.4(KCNH2):c.1582_1603del (p.Arg528fs)	KCNH2	Pathogenic	criteria provided, single submitter
200407	NM_000238.4(KCNH2):c.2104C>T (p.Gln702Ter)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
200693	NM_000238.4(KCNH2):c.2959_2960del (p.Leu987fs)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
200799	NM_000238.4(KCNH2):c.3017del (p.Gly1006fs)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
519524	NM_000238.4(KCNH2):c.3193C>T (p.Gln1065Ter)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67177	NM_000238.4(KCNH2):c.127T>G (p.Tyr43Asp)	KCNH2	Pathogenic	criteria provided, single submitter
67195	NM_000238.4(KCNH2):c.140G>T (p.Gly47Val)	KCNH2	Pathogenic	criteria provided, single submitter
67261	NM_000238.4(KCNH2):c.1750G>A (p.Gly584Ser)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67292	NM_000238.4(KCNH2):c.1838C>T (p.Thr613Met)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67315	NM_000238.4(KCNH2):c.1886A>G (p.Asn629Ser)	KCNH2	Pathogenic	criteria provided, multiple submitters, no conflicts
67397	NM_000238.4(KCNH2):c.2414T>G (p.Phe805Cys)	KCNH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67414	NM_000238.4(KCNH2):c.257T>G (p.Leu86Arg)	KCNH2	Pathogenic	criteria provided, single submitter
67574	NM_000891.3(KCNJ2):c.431G>A (p.Gly144Asp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
53086	NM_000218.3(KCNQ1):c.691C>T (p.Arg231Cys)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14436	NM_000238.4(KCNH2):c.1764C>G (p.Asn588Lys)	KCNH2	Likely pathogenic	criteria provided, single submitter
14441	NM_000238.4(KCNH2):c.2842C>T (p.Arg948Cys)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14442	NM_000238.4(KCNH2):c.298C>G (p.Arg100Gly)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446314	NM_000238.4(KCNH2):c.1945+18C>T	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161255	NM_000238.4(KCNH2):c.3139C>T (p.Arg1047Cys)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200342	NM_000238.4(KCNH2):c.1459G>A (p.Gly487Ser)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200354	NM_000238.4(KCNH2):c.1525G>A (p.Asp509Asn)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200475	NM_000238.4(KCNH2):c.2665T>G (p.Leu889Val)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200501	NM_000238.4(KCNH2):c.2780G>T (p.Trp927Leu)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200522	NM_000238.4(KCNH2):c.3094C>T (p.Arg1032Trp)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200529	NM_000238.4(KCNH2):c.3247A>G (p.Thr1083Ala)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200600	NM_000238.4(KCNH2):c.551GCGCGGGCG[1] (p.184GAG[1])	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
200730	NM_000238.4(KCNH2):c.1802G>A (p.Gly601Asp)	KCNH2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 9 · 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
KCNH2	Definitive	Autosomal dominant	short QT syndrome type 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNH2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:51083	Congenital short QT syndrome
KCNJ2	Orphanet:334	Hereditary atrial fibrillation
KCNJ2	Orphanet:37553	Andersen-Tawil syndrome
KCNJ2	Orphanet:51083	Congenital short QT syndrome
KCNQ1	Orphanet:101016	Romano-Ward syndrome
KCNQ1	Orphanet:334	Hereditary atrial fibrillation
KCNQ1	Orphanet:51083	Congenital short QT syndrome
KCNQ1	Orphanet:90647	Jervell and Lange-Nielsen 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
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	gencc,clinvar
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	clinvar
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
KCNQ1	Potassium voltage-gated channel subfamily KQT member 1	Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	3	111.5×	7e-07

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1

Expression context

Cohort genes with no expression data: 0.

3 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
apex of heart	1
cardiac atrium	1
right atrium auricular region	1
dorsal motor nucleus of vagus nerve	1
inferior vagus X ganglion	1
skeletal muscle tissue of rectus abdominis	1
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNH2	211	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
KCNJ2	256	ubiquitous	marker	inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ1	3,235
KCNH2	1,932
KCNJ2	65

Intra-cohort edges

A	B	Sources
KCNH2	KCNQ1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ1	P51787	28
KCNH2	Q12809	24
KCNJ2	P63252	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Potassium Channels	3	134.3×	8e-06	KCNH2, KCNJ2, KCNQ1
Cardiac conduction	3	108.8×	8e-06	KCNH2, KCNJ2, KCNQ1
Phase 3 - rapid repolarisation	2	761.3×	1e-05	KCNH2, KCNQ1
Muscle contraction	3	77.2×	1e-05	KCNH2, KCNJ2, KCNQ1
Neuronal System	3	44.3×	5e-05	KCNH2, KCNJ2, KCNQ1
Voltage gated Potassium channels	2	162.0×	2e-04	KCNH2, KCNQ1
Sensory perception of sour taste	1	1903.3×	0.002	KCNJ2
Classical Kir channels	1	951.7×	0.003	KCNJ2
G protein gated Potassium channels	1	380.7×	0.006	KCNJ2
Phase 2 - plateau phase	1	253.8×	0.008	KCNQ1
Inwardly rectifying K+ channels	1	237.9×	0.008	KCNJ2
Phase 4 - resting membrane potential	1	200.3×	0.008	KCNJ2
Activation of GABAB receptors	1	200.3×	0.008	KCNJ2
GABA B receptor activation	1	181.3×	0.008	KCNJ2
Activation of G protein gated Potassium channels	1	131.3×	0.010	KCNJ2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	131.3×	0.010	KCNJ2
Sensory perception of taste	1	112.0×	0.011	KCNJ2
GABA receptor activation	1	105.7×	0.011	KCNJ2
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.033	KCNJ2
Sensory Perception	1	31.7×	0.033	KCNJ2
Transmission across Chemical Synapses	1	25.4×	0.039	KCNJ2

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
membrane repolarization during action potential	3	1685.2×	5e-09	KCNH2, KCNJ2, KCNQ1
membrane repolarization during cardiac muscle cell action potential	3	1685.2×	5e-09	KCNH2, KCNJ2, KCNQ1
regulation of membrane repolarization	3	1296.3×	8e-09	KCNH2, KCNJ2, KCNQ1
positive regulation of potassium ion transmembrane transport	3	991.3×	2e-08	KCNH2, KCNJ2, KCNQ1
regulation of heart rate by cardiac conduction	3	374.5×	2e-07	KCNH2, KCNJ2, KCNQ1
potassium ion import across plasma membrane	3	366.4×	2e-07	KCNH2, KCNJ2, KCNQ1
potassium ion transmembrane transport	3	135.9×	4e-06	KCNH2, KCNJ2, KCNQ1
membrane repolarization during ventricular cardiac muscle cell action potential	2	1123.5×	8e-06	KCNH2, KCNQ1
potassium ion export across plasma membrane	2	702.2×	2e-05	KCNH2, KCNQ1
ventricular cardiac muscle cell action potential	2	660.9×	2e-05	KCNH2, KCNQ1
regulation of ventricular cardiac muscle cell membrane repolarization	2	561.7×	3e-05	KCNH2, KCNQ1
potassium ion homeostasis	2	510.7×	3e-05	KCNH2, KCNQ1
cardiac muscle contraction	2	267.5×	1e-04	KCNH2, KCNQ1
cellular response to xenobiotic stimulus	2	160.5×	3e-04	KCNH2, KCNQ1
regulation of membrane potential	2	153.9×	3e-04	KCNH2, KCNQ1
potassium ion transport	2	127.7×	4e-04	KCNH2, KCNJ2
gastrin-induced gastric acid secretion	1	5617.3×	7e-04	KCNQ1
regulation of skeletal muscle contraction via regulation of action potential	1	5617.3×	7e-04	KCNJ2
negative regulation of voltage-gated potassium channel activity	1	5617.3×	7e-04	KCNQ1
regulation of heart rate by hormone	1	2808.7×	0.001	KCNH2
rhythmic behavior	1	2808.7×	0.001	KCNQ1
corticosterone secretion	1	2808.7×	0.001	KCNQ1
stomach development	1	2808.7×	0.001	KCNQ1
regulation of gastric acid secretion	1	1872.4×	0.002	KCNQ1
relaxation of skeletal muscle	1	1872.4×	0.002	KCNJ2
membrane repolarization during atrial cardiac muscle cell action potential	1	936.2×	0.003	KCNQ1
negative regulation of delayed rectifier potassium channel activity	1	936.2×	0.003	KCNQ1
iodide transport	1	802.5×	0.003	KCNQ1
regulation of atrial cardiac muscle cell membrane repolarization	1	802.5×	0.003	KCNQ1
negative regulation of potassium ion export across plasma membrane	1	802.5×	0.003	KCNH2

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) 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
KCNH2	CETIRIZINE
KCNQ1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
KCNQ1	15	4
KCNJ2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	KCNH2
BEPRIDIL	4	KCNH2
BEXAROTENE	4	KCNH2
CLOTRIMAZOLE	4	KCNH2
MORICIZINE	4	KCNH2
PROPIVERINE	4	KCNH2
SUVOREXANT	4	KCNH2
ACETOPHENAZINE	4	KCNH2
DIBUCAINE	4	KCNH2
MESORIDAZINE	4	KCNH2
NIRAPARIB	4	KCNH2
BUPIVACAINE	4	KCNH2
IMIPRAMINE	4	KCNH2
BIPERIDEN	4	KCNH2
EPINASTINE	4	KCNH2
HALOFANTRINE	4	KCNH2
DROPERIDOL	4	KCNH2
RIMONABANT	4	KCNH2
ALOSETRON	4	KCNH2
ARIPIPRAZOLE	4	KCNH2
AMOXAPINE	4	KCNH2
IDARUBICIN	4	KCNH2
DICYCLOMINE	4	KCNH2
TELITHROMYCIN	4	KCNH2
EZETIMIBE	4	KCNH2
SAQUINAVIR	4	KCNH2
VINCAMINE	4	KCNH2
PONATINIB	4	KCNH2
DESLORATADINE	4	KCNH2
PRUCALOPRIDE	4	KCNH2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNH2	4,851	Binding:3558, Toxicity:1071, Functional:169, ADMET:53
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5
KCNJ2	31	Binding:23, ADMET:8

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
KCNH2	4,851
KCNQ1	179

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

30 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)
CETIRIZINE	4	KCNH2
BEPRIDIL	4	KCNH2
BEXAROTENE	4	KCNH2
CLOTRIMAZOLE	4	KCNH2
MORICIZINE	4	KCNH2
PROPIVERINE	4	KCNH2
SUVOREXANT	4	KCNH2
ACETOPHENAZINE	4	KCNH2
DIBUCAINE	4	KCNH2
MESORIDAZINE	4	KCNH2
NIRAPARIB	4	KCNH2
BUPIVACAINE	4	KCNH2
IMIPRAMINE	4	KCNH2
BIPERIDEN	4	KCNH2
EPINASTINE	4	KCNH2
HALOFANTRINE	4	KCNH2
DROPERIDOL	4	KCNH2
RIMONABANT	4	KCNH2
ALOSETRON	4	KCNH2
ARIPIPRAZOLE	4	KCNH2
AMOXAPINE	4	KCNH2
IDARUBICIN	4	KCNH2
DICYCLOMINE	4	KCNH2
TELITHROMYCIN	4	KCNH2
EZETIMIBE	4	KCNH2
SAQUINAVIR	4	KCNH2
VINCAMINE	4	KCNH2
PONATINIB	4	KCNH2
DESLORATADINE	4	KCNH2
PRUCALOPRIDE	4	KCNH2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KCNH2, KCNQ1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	KCNJ2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
KCNJ2	31	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.