Polymorphic ventricular tachycardia

Summary

Polymorphic ventricular tachycardia (MONDO:0020575) is a disease with 3 cohort genes and 3 clinical trials. The dominant Reactome pathway is Cardiac conduction (3 cohort genes).

At a glance

• Cohort genes: 3
• ClinVar variants: 7
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polymorphic ventricular tachycardia
Mondo ID	MONDO:0020575
ICD-11	16452928
NCIT	C111648
SNOMED CT	251159007
UMLS	C0344432
MedGen	138002
Is cancer (heuristic)	no

Also known as: polymorphic ventricular tachycardia · ventricular tachycardia, polymorphic

Data availability: 7 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › ventricular tachycardia › polymorphic ventricular tachycardia

Related subtypes (2): torsades de pointes, ventricular tachycardia, familial

Subtypes (1): catecholaminergic polymorphic ventricular tachycardia

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

7 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
162814	NM_001232.4(CASQ2):c.567C>G (p.Phe189Leu)	CASQ2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
923807	NM_000218.3(KCNQ1):c.1904G>A (p.Gly635Glu)	KCNQ1	Uncertain significance	criteria provided, multiple submitters, no conflicts
228915	NM_000257.4(MYH7):c.5191G>A (p.Asp1731Asn)	LOC126861897	Uncertain significance	criteria provided, multiple submitters, no conflicts
161382	NM_001035.3(RYR2):c.556G>A (p.Val186Met)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
161383	NM_001035.3(RYR2):c.1396C>G (p.Pro466Ala)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
161384	NM_001035.3(RYR2):c.13666G>A (p.Ala4556Thr)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
191379	NM_001035.3(RYR2):c.5657dup (p.Lys1887fs)	RYR2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RYR2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
RYR2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
RYR2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
RYR2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CASQ2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
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
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-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)
RYR2	Ryanodine receptor 2	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction.
CASQ2	Calsequestrin-2	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.
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: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	2	74.3×	5e-04
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
CASQ2	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_sf
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
heart right ventricle	2
left ventricle myocardium	2
myocardium	2
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
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
CASQ2	213	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
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
RYR2	2,653
CASQ2	1,977

Intra-cohort edges

A	B	Sources
CASQ2	RYR2	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
RYR2	Q92736	26
CASQ2	O14958	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Cardiac conduction	3	108.8×	8e-06	RYR2, CASQ2, KCNQ1
Muscle contraction	3	77.2×	1e-05	RYR2, CASQ2, KCNQ1
Ion homeostasis	2	135.9×	3e-04	RYR2, CASQ2
Stimuli-sensing channels	2	90.6×	4e-04	RYR2, CASQ2
Ion channel transport	2	64.0×	7e-04	RYR2, CASQ2
Phase 3 - rapid repolarisation	1	380.7×	0.005	KCNQ1
Phase 2 - plateau phase	1	253.8×	0.006	KCNQ1
Transport of small molecules	2	16.8×	0.006	RYR2, CASQ2
Voltage gated Potassium channels	1	81.0×	0.015	KCNQ1
Potassium Channels	1	44.8×	0.024	KCNQ1
Neuronal System	1	14.8×	0.066	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Purkinje myocyte to ventricular cardiac muscle cell signaling	2	5617.3×	1e-06	RYR2, CASQ2
cardiac muscle contraction	3	401.2×	1e-06	RYR2, CASQ2, KCNQ1
cellular response to caffeine	2	1021.3×	3e-05	RYR2, CASQ2
regulation of membrane repolarization	2	864.2×	3e-05	CASQ2, KCNQ1
cellular response to epinephrine stimulus	2	864.2×	3e-05	RYR2, KCNQ1
detection of calcium ion	2	749.0×	3e-05	RYR2, CASQ2
ventricular cardiac muscle cell action potential	2	660.9×	4e-05	RYR2, KCNQ1
striated muscle contraction	2	561.7×	5e-05	RYR2, CASQ2
positive regulation of heart rate	2	468.1×	6e-05	RYR2, KCNQ1
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	2	449.4×	6e-05	RYR2, CASQ2
regulation of heart rate	2	312.1×	1e-04	RYR2, CASQ2
gastrin-induced gastric acid secretion	1	5617.3×	0.001	KCNQ1
establishment of protein localization to endoplasmic reticulum	1	5617.3×	0.001	RYR2
negative regulation of voltage-gated potassium channel activity	1	5617.3×	0.001	KCNQ1
regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1	5617.3×	0.001	CASQ2
intracellular calcium ion homeostasis	2	96.8×	0.001	RYR2, CASQ2
rhythmic behavior	1	2808.7×	0.002	KCNQ1
corticosterone secretion	1	2808.7×	0.002	KCNQ1
stomach development	1	2808.7×	0.002	KCNQ1
regulation of gastric acid secretion	1	1872.4×	0.002	KCNQ1
type B pancreatic cell apoptotic process	1	1872.4×	0.002	RYR2
regulation of AV node cell action potential	1	1872.4×	0.002	RYR2
regulation of atrial cardiac muscle cell action potential	1	1872.4×	0.002	RYR2
left ventricular cardiac muscle tissue morphogenesis	1	1404.3×	0.003	RYR2
obsolete positive regulation of sequestering of calcium ion	1	1404.3×	0.003	RYR2
obsolete sequestering of calcium ion	1	1123.5×	0.003	CASQ2
sarcoplasmic reticulum calcium ion transport	1	1123.5×	0.003	RYR2
positive regulation of the force of heart contraction	1	1123.5×	0.003	RYR2
regulation of SA node cell action potential	1	936.2×	0.003	RYR2
membrane repolarization during atrial cardiac muscle cell action potential	1	936.2×	0.003	KCNQ1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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
KCNQ1	AMBRISENTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ1	15	4
RYR2	1	2
CASQ2	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
ALADORIAN	2	RYR2

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
RYR2	15	Binding:15

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: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

16 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
ALADORIAN	2	RYR2

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	1	RYR2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CASQ2

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)
CASQ2	0	RYR2

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03963271	Not specified	UNKNOWN	Noninvasive Electrocardiographic Imaging for Individuals at Risk for Apparently Idiopathic Ventricular Fibrillation.
NCT04548804	Not specified	UNKNOWN	Better Mechanistic Understanding of and Risk Stratification for Ventricular Tachyarrhythmias Through ECGI
NCT07130175	Not specified	COMPLETED	Radiofrequency Ablation for Polymorphic Ventricular Tachycardia With Heart Failure (RFCA for PMVT-HF)