Catecholaminergic polymorphic ventricular tachycardia 2

Summary

Catecholaminergic polymorphic ventricular tachycardia 2 (MONDO:0012762) is a disease caused by CASQ2 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: CASQ2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 229
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	catecholaminergic polymorphic ventricular tachycardia 2
Mondo ID	MONDO:0012762
OMIM	611938
DOID	DOID:0060676
NCIT	C148368
UMLS	C2677794
MedGen	393837
GARD	0015535
Is cancer (heuristic)	no

Also known as: CASQ2 catecholaminergic polymorphic ventricular tachycardia · catecholaminergic polymorphic ventricular tachycardia 2 · catecholaminergic polymorphic ventricular tachycardia caused by mutation in CASQ2 · catecholaminergic polymorphic ventricular tachycardia type 2 · CPVT2 · ventricular tachycardia, catecholaminergic polymorphic, 2 · ventricular tachycardia, catecholaminergic polymorphic, type 2

Data availability: 229 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › catecholaminergic polymorphic ventricular tachycardia › catecholaminergic polymorphic ventricular tachycardia 2

Related subtypes (6): catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia 3, catecholaminergic polymorphic ventricular tachycardia 4, catecholaminergic polymorphic ventricular tachycardia 5, long QT syndrome 16, ventricular tachycardia, catecholaminergic polymorphic 6

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

229 retrieved; paginated sample, class counts are floors:

104 uncertain significance, 30 conflicting classifications of pathogenicity, 26 likely benign, 21 benign/likely benign, 16 pathogenic/likely pathogenic, 13 likely pathogenic, 13 benign, 6 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033372	NM_001232.4(CASQ2):c.737+2T>A	CASQ2	Pathogenic	criteria provided, single submitter
1367739	NM_001232.4(CASQ2):c.576C>A (p.Tyr192Ter)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455253	NM_001232.4(CASQ2):c.939+5G>C	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1746831	NM_001232.4(CASQ2):c.532+1G>A	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1757434	NM_001232.4(CASQ2):c.715G>T (p.Glu239Ter)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17610	NM_001232.4(CASQ2):c.919G>C (p.Asp307His)	CASQ2	Pathogenic	no assertion criteria provided
17611	NM_001232.4(CASQ2):c.339_354del (p.Ser113fs)	CASQ2	Pathogenic	criteria provided, multiple submitters, no conflicts
17612	NM_001232.4(CASQ2):c.500T>A (p.Leu167His)	CASQ2	Pathogenic	no assertion criteria provided
190743	NM_001232.4(CASQ2):c.606+1G>C	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190755	NM_001232.4(CASQ2):c.923C>T (p.Pro308Leu)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190759	NM_001232.4(CASQ2):c.213del (p.Gln71fs)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202832	NM_001232.4(CASQ2):c.737+1G>A	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222522	NM_001232.4(CASQ2):c.546del (p.Phe182fs)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236407	NM_001232.4(CASQ2):c.320-2A>G	CASQ2	Pathogenic	criteria provided, multiple submitters, no conflicts
41042	NM_001232.4(CASQ2):c.62del (p.Glu21fs)	CASQ2	Pathogenic	criteria provided, single submitter
41043	NM_001232.4(CASQ2):c.97C>T (p.Arg33Ter)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427946	NM_001232.4(CASQ2):c.164A>G (p.Tyr55Cys)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427947	NM_001232.4(CASQ2):c.783G>A (p.Trp261Ter)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488772	NM_001232.4(CASQ2):c.115G>T (p.Glu39Ter)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
519365	NM_001232.4(CASQ2):c.939+1G>T	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801535	NM_001232.4(CASQ2):c.381C>T (p.Gly127=)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
862119	NM_001232.4(CASQ2):c.98G>A (p.Arg33Gln)	CASQ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324014	NM_001232.4(CASQ2):c.319+1G>A	CASQ2	Likely pathogenic	criteria provided, single submitter
228247	NM_001232.4(CASQ2):c.940-1G>T	CASQ2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2438853	NM_001232.4(CASQ2):c.607-1G>A	CASQ2	Likely pathogenic	criteria provided, single submitter
2505552	NM_001232.4(CASQ2):c.736A>T (p.Arg246Ter)	CASQ2	Likely pathogenic	criteria provided, single submitter
2506578	NM_001232.4(CASQ2):c.268_269insTA (p.Gly90fs)	CASQ2	Likely pathogenic	criteria provided, single submitter
3263466	NM_001232.4(CASQ2):c.533-2A>G	CASQ2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3575248	NM_001232.4(CASQ2):c.738-1G>T	CASQ2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3575384	NM_001232.4(CASQ2):c.606+2T>A	CASQ2	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
CASQ2	Definitive	Autosomal recessive	catecholaminergic polymorphic ventricular tachycardia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASQ2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-2	gencc,clinvar
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASQ2	Calsequestrin-2	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASQ2	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_sf
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	2
left ventricle myocardium	2
myocardium	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASQ2	213	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RYR2	2,653
CASQ2	1,977

Intra-cohort edges

A	B	Sources
CASQ2	RYR2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RYR2	Q92736	26
CASQ2	O14958	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Ion homeostasis	2	203.9×	1e-04	CASQ2, RYR2
Stimuli-sensing channels	2	135.9×	2e-04	CASQ2, RYR2
Cardiac conduction	2	108.8×	2e-04	CASQ2, RYR2
Ion channel transport	2	96.0×	2e-04	CASQ2, RYR2
Muscle contraction	2	77.2×	2e-04	CASQ2, RYR2
Transport of small molecules	2	25.1×	0.002	CASQ2, RYR2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Purkinje myocyte to ventricular cardiac muscle cell signaling	2	8426.0×	3e-07	CASQ2, RYR2
cellular response to caffeine	2	1532.0×	9e-06	CASQ2, RYR2
detection of calcium ion	2	1123.5×	1e-05	CASQ2, RYR2
striated muscle contraction	2	842.6×	2e-05	CASQ2, RYR2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	2	674.1×	2e-05	CASQ2, RYR2
regulation of heart rate	2	468.1×	3e-05	CASQ2, RYR2
cardiac muscle contraction	2	401.2×	4e-05	CASQ2, RYR2
intracellular calcium ion homeostasis	2	145.3×	3e-04	CASQ2, RYR2
establishment of protein localization to endoplasmic reticulum	1	8426.0×	5e-04	RYR2
regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1	8426.0×	5e-04	CASQ2
type B pancreatic cell apoptotic process	1	2808.7×	0.001	RYR2
regulation of AV node cell action potential	1	2808.7×	0.001	RYR2
regulation of atrial cardiac muscle cell action potential	1	2808.7×	0.001	RYR2
left ventricular cardiac muscle tissue morphogenesis	1	2106.5×	0.001	RYR2
obsolete positive regulation of sequestering of calcium ion	1	2106.5×	0.001	RYR2
obsolete sequestering of calcium ion	1	1685.2×	0.001	CASQ2
sarcoplasmic reticulum calcium ion transport	1	1685.2×	0.001	RYR2
positive regulation of the force of heart contraction	1	1685.2×	0.001	RYR2
regulation of SA node cell action potential	1	1404.3×	0.002	RYR2
regulation of cell communication by electrical coupling	1	1203.7×	0.002	CASQ2
response to caffeine	1	1203.7×	0.002	RYR2
embryonic heart tube morphogenesis	1	936.2×	0.002	RYR2
negative regulation of potassium ion transport	1	936.2×	0.002	CASQ2
cardiac muscle hypertrophy	1	842.6×	0.002	RYR2
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	842.6×	0.002	RYR2
cell communication by electrical coupling involved in cardiac conduction	1	702.2×	0.002	RYR2
regulation of ventricular cardiac muscle cell action potential	1	702.2×	0.002	RYR2
regulation of cardiac muscle contraction by calcium ion signaling	1	648.1×	0.002	RYR2
response to redox state	1	648.1×	0.002	RYR2
regulation of membrane repolarization	1	648.1×	0.002	CASQ2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR2	1	2
CASQ2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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
RYR2	15	Binding:15

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

1 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)
ALADORIAN	2	RYR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06661278	Not specified	RECRUITING	Evaluation of Exercise Testing and Physical Activity in Children and Adolescents Living With Inherited Arrhythmias