Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Summary

Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (MONDO:0020745) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 262

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome
Mondo ID	MONDO:0020745
OMIM	115000
UMLS	C5542154
MedGen	1781114
Is cancer (heuristic)	no

Also known as: autosomal dominant cardiac arrhythmia (Kuhn) · VACRDS · ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Data availability: 262 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

262 retrieved; paginated sample, class counts are floors:

169 uncertain significance, 68 conflicting classifications of pathogenicity, 11 benign/likely benign, 6 likely pathogenic, 6 likely benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1119950	NM_001035.3(RYR2):c.11983A>C (p.Ile3995Leu)	RYR2	Pathogenic	no assertion criteria provided
852605	NM_001035.3(RYR2):c.13937A>C (p.Asp4646Ala)	RYR2	Pathogenic	criteria provided, single submitter
1119951	NM_001035.3(RYR2):c.12587C>T (p.Thr4196Ile)	LOC126806068	Likely pathogenic	criteria provided, single submitter
1480581	NM_001035.3(RYR2):c.11623G>T (p.Val3875Leu)	RYR2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441802	NM_001035.3(RYR2):c.11805G>C (p.Leu3935Phe)	RYR2	Likely pathogenic	criteria provided, single submitter
3065287	NM_001035.3(RYR2):c.9931_9934del (p.Lys3311fs)	RYR2	Likely pathogenic	criteria provided, single submitter
3382069	NM_001035.3(RYR2):c.10835C>T (p.Pro3612Leu)	RYR2	Likely pathogenic	criteria provided, single submitter
3391121	NM_001035.3(RYR2):c.11794C>G (p.Gln3932Glu)	RYR2	Likely pathogenic	criteria provided, single submitter
201242	NM_001035.3(RYR2):c.3950C>T (p.Thr1317Met)	LOC126806067	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201381	NM_001035.3(RYR2):c.4094C>T (p.Ala1365Val)	LOC126806067	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
532318	NM_001035.3(RYR2):c.3883A>G (p.Ser1295Gly)	LOC126806067	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
574960	NM_001035.3(RYR2):c.3877C>G (p.Gln1293Glu)	LOC126806067	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003245	NM_001035.3(RYR2):c.12638A>G (p.Glu4213Gly)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1014648	NM_001035.3(RYR2):c.12865A>G (p.Ser4289Gly)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1332236	NM_001035.3(RYR2):c.12664G>A (p.Glu4222Lys)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
201411	NM_001035.3(RYR2):c.12667_12669del (p.Lys4223del)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
222794	NM_001035.3(RYR2):c.12837G>A (p.Met4279Ile)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
404179	NM_001035.3(RYR2):c.12463T>A (p.Ser4155Thr)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
499175	NM_001035.3(RYR2):c.12541G>A (p.Gly4181Arg)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
927712	NM_001035.3(RYR2):c.12920G>A (p.Arg4307His)	LOC126806068	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1046429	NM_001035.3(RYR2):c.6811G>T (p.Gly2271Cys)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1060539	NM_001035.3(RYR2):c.5311A>G (p.Ile1771Val)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315719	NM_001035.3(RYR2):c.5662C>T (p.Arg1888Trp)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
165105	NM_001035.3(RYR2):c.6983C>T (p.Pro2328Leu)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1762571	NM_001035.3(RYR2):c.8238A>G (p.Ile2746Met)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178115	NM_001035.3(RYR2):c.1939C>T (p.Arg647Cys)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179410	NM_001035.3(RYR2):c.4241G>A (p.Arg1414Gln)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179911	NM_001035.3(RYR2):c.3225C>T (p.Ala1075=)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180485	NM_001035.3(RYR2):c.1318G>A (p.Ala440Thr)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191492	NM_001035.3(RYR2):c.13712C>T (p.Thr4571Met)	RYR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · 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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	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.

Protein-family classification

Druggable: 1 · 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	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
left ventricle myocardium	1
myocardium	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RYR2	2,653

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RYR2	Q92736	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 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
Ion homeostasis	1	203.9×	0.016	RYR2
Stimuli-sensing channels	1	135.9×	0.016	RYR2
Cardiac conduction	1	108.8×	0.016	RYR2
Ion channel transport	1	96.0×	0.016	RYR2
Muscle contraction	1	77.2×	0.016	RYR2
Transport of small molecules	1	25.1×	0.040	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
establishment of protein localization to endoplasmic reticulum	1	16852.0×	0.001	RYR2
Purkinje myocyte to ventricular cardiac muscle cell signaling	1	8426.0×	0.001	RYR2
type B pancreatic cell apoptotic process	1	5617.3×	0.001	RYR2
regulation of AV node cell action potential	1	5617.3×	0.001	RYR2
regulation of atrial cardiac muscle cell action potential	1	5617.3×	0.001	RYR2
left ventricular cardiac muscle tissue morphogenesis	1	4213.0×	0.001	RYR2
obsolete positive regulation of sequestering of calcium ion	1	4213.0×	0.001	RYR2
sarcoplasmic reticulum calcium ion transport	1	3370.4×	0.001	RYR2
positive regulation of the force of heart contraction	1	3370.4×	0.001	RYR2
regulation of SA node cell action potential	1	2808.7×	0.001	RYR2
response to caffeine	1	2407.4×	0.001	RYR2
embryonic heart tube morphogenesis	1	1872.4×	0.001	RYR2
cardiac muscle hypertrophy	1	1685.2×	0.001	RYR2
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	1685.2×	0.001	RYR2
cellular response to caffeine	1	1532.0×	0.001	RYR2
cell communication by electrical coupling involved in cardiac conduction	1	1404.3×	0.001	RYR2
regulation of ventricular cardiac muscle cell action potential	1	1404.3×	0.001	RYR2
regulation of cardiac muscle contraction by calcium ion signaling	1	1296.3×	0.001	RYR2
response to redox state	1	1296.3×	0.001	RYR2
cellular response to epinephrine stimulus	1	1296.3×	0.001	RYR2
calcium ion transport into cytosol	1	1203.7×	0.002	RYR2
detection of calcium ion	1	1123.5×	0.002	RYR2
ventricular cardiac muscle cell action potential	1	991.3×	0.002	RYR2
regulation of cardiac muscle contraction	1	887.0×	0.002	RYR2
striated muscle contraction	1	842.6×	0.002	RYR2
response to muscle stretch	1	766.0×	0.002	RYR2
positive regulation of heart rate	1	702.2×	0.002	RYR2
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.002	RYR2
response to muscle activity	1	581.1×	0.002	RYR2
regulation of heart rate	1	468.1×	0.003	RYR2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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

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: 1; 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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.