short QT syndrome type 2

Summary

short QT syndrome type 2 (MONDO:0012313) is a disease caused by KCNQ1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: KCNQ1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 203

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short QT syndrome type 2
Mondo ID	MONDO:0012313
MeSH	C566505
OMIM	609621
UMLS	C1865019
MedGen	355890
GARD	0018634
Is cancer (heuristic)	no

Also known as: KCNQ1 short QT syndrome · short QT syndrome 2 · short QT syndrome caused by mutation in KCNQ1 · short QT syndrome type 2 · SQT2

Data availability: 203 ClinVar variants · 2 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 2

Related subtypes (3): short QT syndrome type 1, 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

203 retrieved; paginated sample, class counts are floors:

64 uncertain significance, 53 conflicting classifications of pathogenicity, 26 benign/likely benign, 21 pathogenic/likely pathogenic, 16 pathogenic, 10 benign, 7 likely benign, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1452627	NM_000218.3(KCNQ1):c.771_775dup (p.Arg259fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3118	NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)	KCNQ1	Pathogenic	reviewed by expert panel
3144	NM_000218.3(KCNQ1):c.805G>A (p.Gly269Ser)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
3382790	NM_000218.3(KCNQ1):c.744G>A (p.Trp248Ter)	KCNQ1	Pathogenic	criteria provided, single submitter
375594	NM_000218.3(KCNQ1):c.835T>A (p.Phe279Ile)	KCNQ1	Pathogenic	no assertion criteria provided
449221	NM_000218.3(KCNQ1):c.200_210del (p.Pro67fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52930	NM_000218.3(KCNQ1):c.1014CTT[1] (p.Phe340del)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52950	NM_000218.3(KCNQ1):c.1075C>T (p.Gln359Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52953	NM_000218.3(KCNQ1):c.1085A>G (p.Lys362Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52974	NM_000218.3(KCNQ1):c.1265dup (p.Phe423fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52978	NM_000218.3(KCNQ1):c.1343dup (p.Glu449fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52983	NM_000218.3(KCNQ1):c.1486_1487del (p.Leu496fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52996	NM_000218.3(KCNQ1):c.1588C>T (p.Gln530Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
52998	NM_000218.3(KCNQ1):c.1615C>T (p.Arg539Trp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53003	NM_000218.3(KCNQ1):c.1664G>A (p.Arg555His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53006	NM_000218.3(KCNQ1):c.1697C>T (p.Ser566Phe)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53009	NM_000218.3(KCNQ1):c.1702G>A (p.Gly568Arg)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53018	NM_000218.3(KCNQ1):c.1781G>A (p.Arg594Gln)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53025	NM_000218.3(KCNQ1):c.1892_1911del (p.Pro631fs)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53052	NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53056	NM_000218.3(KCNQ1):c.513C>G (p.Tyr171Ter)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53058	NM_000218.3(KCNQ1):c.520C>T (p.Arg174Cys)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53059	NM_000218.3(KCNQ1):c.521G>A (p.Arg174His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53070	NM_000218.3(KCNQ1):c.568C>T (p.Arg190Trp)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53077	NM_000218.3(KCNQ1):c.604G>A (p.Asp202Asn)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53084	NM_000218.3(KCNQ1):c.683+5G>A	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53087	NM_000218.3(KCNQ1):c.692G>A (p.Arg231His)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53101	NM_000218.3(KCNQ1):c.776G>A (p.Arg259His)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
53107	NM_000218.3(KCNQ1):c.796del (p.Leu266fs)	KCNQ1	Pathogenic	criteria provided, multiple submitters, no conflicts
53108	NM_000218.3(KCNQ1):c.797T>C (p.Leu266Pro)	KCNQ1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
KCNQ1	Strong	Autosomal dominant	short QT syndrome type 2	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
KCNQ1OT1	Orphanet:2128	Isolated hemihyperplasia
KCNQ1OT1	Orphanet:231117	Beckwith-Wiedemann syndrome due to imprinting defect of 11p15

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ1	HGNC:6294	ENSG00000053918	P51787	Potassium voltage-gated channel subfamily KQT member 1	gencc,clinvar
KCNQ1-AS1	HGNC:42790	ENSG00000229414		KCNQ1 antisense RNA 1	clinvar
KCNQ1OT1	HGNC:6295	ENSG00000269821		KCNQ1 opposite strand/antisense transcript 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	1	37.2×	0.053
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNQ1	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1
KCNQ1-AS1	Other/Unknown	no
KCNQ1OT1	Other/Unknown	no

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
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
hindlimb stylopod muscle	1
leukocyte	1
right ovary	1
cardiac muscle of right atrium	1
kidney epithelium	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNQ1	132	broad	marker	left adrenal gland cortex, left adrenal gland, right adrenal gland cortex
KCNQ1-AS1	87		yes	right ovary, hindlimb stylopod muscle, leukocyte
KCNQ1OT1	194	ubiquitous	marker	tibia, cardiac muscle of right atrium, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ1	3,235
KCNQ1-AS1	0
KCNQ1OT1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ1	P51787	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phase 3 - rapid repolarisation	1	1142.0×	0.005	KCNQ1
Phase 2 - plateau phase	1	761.3×	0.005	KCNQ1
Voltage gated Potassium channels	1	243.0×	0.010	KCNQ1
Potassium Channels	1	134.3×	0.013	KCNQ1
Cardiac conduction	1	108.8×	0.013	KCNQ1
Muscle contraction	1	77.2×	0.015	KCNQ1
Neuronal System	1	44.3×	0.023	KCNQ1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gastrin-induced gastric acid secretion	1	16852.0×	0.001	KCNQ1
negative regulation of voltage-gated potassium channel activity	1	16852.0×	0.001	KCNQ1
rhythmic behavior	1	8426.0×	0.001	KCNQ1
corticosterone secretion	1	8426.0×	0.001	KCNQ1
stomach development	1	8426.0×	0.001	KCNQ1
regulation of gastric acid secretion	1	5617.3×	0.002	KCNQ1
membrane repolarization during atrial cardiac muscle cell action potential	1	2808.7×	0.002	KCNQ1
negative regulation of delayed rectifier potassium channel activity	1	2808.7×	0.002	KCNQ1
iodide transport	1	2407.4×	0.002	KCNQ1
regulation of atrial cardiac muscle cell membrane repolarization	1	2407.4×	0.002	KCNQ1
positive regulation of cardiac muscle contraction	1	2106.5×	0.002	KCNQ1
auditory receptor cell development	1	1872.4×	0.002	KCNQ1
adrenergic receptor signaling pathway	1	1872.4×	0.002	KCNQ1
intracellular chloride ion homeostasis	1	1685.2×	0.002	KCNQ1
renal absorption	1	1685.2×	0.002	KCNQ1
cardiac muscle cell contraction	1	1685.2×	0.002	KCNQ1
membrane repolarization during action potential	1	1685.2×	0.002	KCNQ1
membrane repolarization during cardiac muscle cell action potential	1	1685.2×	0.002	KCNQ1
atrial cardiac muscle cell action potential	1	1685.2×	0.002	KCNQ1
membrane repolarization during ventricular cardiac muscle cell action potential	1	1685.2×	0.002	KCNQ1
regulation of membrane repolarization	1	1296.3×	0.002	KCNQ1
cellular response to epinephrine stimulus	1	1296.3×	0.002	KCNQ1
intestinal absorption	1	1203.7×	0.002	KCNQ1
potassium ion export across plasma membrane	1	1053.2×	0.002	KCNQ1
renal sodium ion absorption	1	991.3×	0.002	KCNQ1
ventricular cardiac muscle cell action potential	1	991.3×	0.002	KCNQ1
positive regulation of potassium ion transmembrane transport	1	991.3×	0.002	KCNQ1
detection of mechanical stimulus involved in sensory perception of sound	1	936.2×	0.002	KCNQ1
regulation of ventricular cardiac muscle cell membrane repolarization	1	842.6×	0.002	KCNQ1
potassium ion homeostasis	1	766.0×	0.002	KCNQ1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
KCNQ1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ1	15	4
KCNQ1-AS1	0	0
KCNQ1OT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNQ1
PALONOSETRON	4	KCNQ1
DARUNAVIR	4	KCNQ1
DARIFENACIN	4	KCNQ1
TOLTERODINE	4	KCNQ1
SOLIFENACIN	4	KCNQ1
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNQ1
SUNITINIB	4	KCNQ1
NELFINAVIR	4	KCNQ1
VOLINANSERIN	3	KCNQ1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNQ1	179	Binding:96, Functional:64, ADMET:14, Toxicity:5

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
KCNQ1	179

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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)
AMBRISENTAN	4	KCNQ1
DULOXETINE	4	KCNQ1
PALONOSETRON	4	KCNQ1
DARUNAVIR	4	KCNQ1
DARIFENACIN	4	KCNQ1
TOLTERODINE	4	KCNQ1
SOLIFENACIN	4	KCNQ1
EVEROLIMUS	4	KCNQ1
RALTEGRAVIR	4	KCNQ1
MARAVIROC	4	KCNQ1
ALVIMOPAN	4	KCNQ1
NEBIVOLOL	4	KCNQ1
SUNITINIB	4	KCNQ1
NELFINAVIR	4	KCNQ1
VOLINANSERIN	3	KCNQ1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNQ1
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	2	KCNQ1-AS1, KCNQ1OT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KCNQ1-AS1	0	—
KCNQ1OT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.