RYR2

ryanodine receptor 2, the group of Ryanodine receptors|EF-hand domain containing|Armadillo like helical domain containing|MicroRNA protein coding host genes

Basic information

Region (hg38): 1:237042183-237833988

Previous symbols: [ "ARVD2" ]

Links

ENSG00000198626 ∙ NCBI:6262 ∙ OMIM:180902 ∙ HGNC:10484 ∙ Uniprot:Q92736 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• catecholaminergic polymorphic ventricular tachycardia 1 (Strong), mode of inheritance: AD
• arrhythmogenic right ventricular dysplasia 2 (Disputed Evidence), mode of inheritance: AD
• arrhythmogenic right ventricular dysplasia 2 (Definitive), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Supportive), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia 1 (Definitive), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia 1 (Strong), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Definitive), mode of inheritance: AD
• hypertrophic cardiomyopathy (Limited), mode of inheritance: AD
• arrhythmogenic right ventricular cardiomyopathy (Refuted Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ventricular tachycardia, catecholaminergic polymorphic, 1, with or without atrial dysfunction and/or dilated cardomyopathy; Arrhythmogenic right ventricular dysplasia, familial, 2; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome	AD	Cardiovascular	Individuals can have increased risk of mortality in untreated Ventricular tachycardia, catecholaminergic polymorphic, and treatment (eg, beta-blockers without sympathomimetic activity) can be effective to reduce syncope, but ICD placement may be needed; In ARVD2, individuals may manifest with syncope, cardiac arrest, and sudden death, and surveillance may allow early diagnosis of sequelae; Preventive measures (eg, with antiarrhythmic pharmacologic agents and/or ICD placement) may be beneficial, though some individuals may require heart transplantation; Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome may involve manifestations such as cardiac arrest and sudden cardiad death, with negative exercise stress testing and adrenaline challenge, and awareness may allow preventive measures and rapid treatment of life-threatening episodes	Cardiovascular	11157710; 11208676; 11159936; 17875969; 20301310; 19926015; 33536282

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RYR2 gene.

• Catecholaminergic polymorphic ventricular tachycardia 1 (55 variants)
• not provided (19 variants)
• Cardiovascular phenotype (7 variants)
• Cardiomyopathy (3 variants)
• Long QT syndrome (3 variants)
• Arrhythmogenic right ventricular dysplasia 2 (2 variants)
• Arrhythmogenic right ventricular dysplasia 2;Catecholaminergic polymorphic ventricular tachycardia 1 (1 variants)
• Arrhythmogenic right ventricular cardiomyopathy (1 variants)
• Catecholaminergic polymorphic ventricular tachycardia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RYR2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			48	1651	12	1711
missense	62	126	3236	52	1	3477
nonsense	1	3	82			86
start loss			1			1
frameshift		5	79	1		85
inframe indel		6	47			53
splice donor/acceptor (+/-2bp)			70	1		71
splice region			189	259	15	463
non coding			52	864	342	1258
Total	63	140	3615	2569	355

Highest pathogenic variant AF is 0.00000659

Variants in RYR2

This is a list of pathogenic ClinVar variants found in the RYR2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-237042215-C-T			Benign (Mar 03, 2015)
1-237042322-C-A			Benign (Jun 26, 2018)
1-237042383-C-A			Benign (Mar 03, 2015)
1-237042383-C-T			Benign (Mar 03, 2015)
1-237042394-A-C			Benign (Mar 03, 2015)
1-237042412-CT-C			Benign (Mar 03, 2015)
1-237042429-C-T			Benign (Mar 03, 2015)
1-237042459-G-T		Catecholaminergic polymorphic ventricular tachycardia 1 • Arrhythmogenic right ventricular dysplasia 2	Conflicting classifications of pathogenicity (Jan 13, 2018)
1-237042458-G-GGCC		not specified	Benign (Mar 25, 2014)
1-237042475-A-C			Benign (Mar 03, 2015)
1-237042476-G-A		not specified	Likely benign (Feb 06, 2018)
1-237042485-G-T		not specified	Likely benign (Jan 08, 2018)
1-237042490-G-C		not specified	Likely benign (Aug 29, 2017)
1-237042492-G-C		not specified	Likely benign (Jul 22, 2016)
1-237042495-C-A		Arrhythmogenic right ventricular cardiomyopathy • Catecholaminergic polymorphic ventricular tachycardia	Uncertain significance (Jun 14, 2016)
1-237042495-C-T		not specified	Likely benign (Jun 26, 2017)
1-237042502-C-A		Catecholaminergic polymorphic ventricular tachycardia • Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (Jun 14, 2016)
1-237042507-A-G		Catecholaminergic polymorphic ventricular tachycardia 1 • Arrhythmogenic right ventricular dysplasia 2 • Cardiomyopathy • Catecholaminergic polymorphic ventricular tachycardia	Uncertain significance (Dec 13, 2023)
1-237042509-G-A		Cardiomyopathy	Uncertain significance (Dec 05, 2022)
1-237042512-G-A		Cardiomyopathy	Uncertain significance (Apr 05, 2021)
1-237042515-C-A		Cardiomyopathy	Uncertain significance (Sep 30, 2019)
1-237042520-C-A		Cardiomyopathy	Uncertain significance (Feb 18, 2020)
1-237042521-C-T		Cardiomyopathy	Uncertain significance (Mar 23, 2021)
1-237042523-T-C			Uncertain significance (Oct 28, 2022)
1-237042525-G-T		Cardiomyopathy	Uncertain significance (Dec 04, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RYR2	protein_coding	protein_coding	ENST00000366574	105	791784

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000805	124610	0	67	124677	0.000269

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	5.78	1804	2.64e+3	0.683	0.000150	32701
Missense in Polyphen		491	932.52	0.52653		11722
Synonymous	-0.195	985	977	1.01	0.0000583	9184
Loss of Function	11.8	50	253	0.197	0.0000138	3259

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000671	0.000663
Ashkenazi Jewish	0.000209	0.000199
East Asian	0.000112	0.000111
Finnish	0.000188	0.000186
European (Non-Finnish)	0.000321	0.000310
Middle Eastern	0.000112	0.000111
South Asian	0.000297	0.000294
Other	0.000336	0.000330

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development. {ECO:0000269|PubMed:10830164, ECO:0000269|PubMed:20056922, ECO:0000269|PubMed:27733687}.
• Disease: DISEASE: Arrhythmogenic right ventricular dysplasia, familial, 2 (ARVD2) [MIM:600996]: A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. {ECO:0000269|PubMed:11159936}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ventricular tachycardia, catecholaminergic polymorphic, 1, with or without atrial dysfunction and/or dilated cardiomyopathy (CPVT1) [MIM:604772]: An arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. CPVT1 inheritance is autosomal dominant. {ECO:0000269|PubMed:11157710, ECO:0000269|PubMed:11208676, ECO:0000269|PubMed:12093772, ECO:0000269|PubMed:12106942, ECO:0000269|PubMed:14571276, ECO:0000269|PubMed:15046072, ECO:0000269|PubMed:15046073, ECO:0000269|PubMed:15466642, ECO:0000269|PubMed:15544015, ECO:0000269|PubMed:16188589, ECO:0000269|PubMed:17984046, ECO:0000269|PubMed:24793461, ECO:0000269|PubMed:25372681, ECO:0000269|PubMed:27733687}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Oxytocin signaling pathway - Homo sapiens (human);Cardiac muscle contraction - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics;Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Pancreatic secretion - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Arrhythmogenic Right Ventricular Cardiomyopathy;Myometrial Relaxation and Contraction Pathways;Cell-type Dependent Selectivity of CCK2R Signaling;Calcium Regulation in the Cardiac Cell;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Stimuli-sensing channels;Ion channel transport;Ion homeostasis;Transport of small molecules;actions of nitric oxide in the heart;Cardiac conduction;Muscle contraction (Consensus)

Recessive Scores

• pRec: 0.279

Intolerance Scores

• loftool: 0.0489
• rvis_EVS: -5.87
• rvis_percentile_EVS: 0.05

Haploinsufficiency Scores

• pHI: 0.273
• hipred: Y
• hipred_score: 0.744
• ghis: 0.516

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.715

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Ryr2
• Phenotype: homeostasis/metabolism phenotype; muscle phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; embryo phenotype; immune system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: response to hypoxia;regulation of heart rate;embryonic heart tube morphogenesis;left ventricular cardiac muscle tissue morphogenesis;cardiac muscle hypertrophy;detection of calcium ion;calcium ion transport;cellular calcium ion homeostasis;positive regulation of heart rate;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;regulation of cardiac muscle contraction by calcium ion signaling;release of sequestered calcium ion into cytosol by sarcoplasmic reticulum;response to muscle activity;calcium-mediated signaling;BMP signaling pathway;response to caffeine;ion transmembrane transport;calcium-mediated signaling using intracellular calcium source;response to muscle stretch;release of sequestered calcium ion into cytosol;positive regulation of sequestering of calcium ion;regulation of cytosolic calcium ion concentration;response to redox state;regulation of cardiac muscle contraction;cardiac muscle contraction;canonical Wnt signaling pathway;calcium ion transport into cytosol;sarcoplasmic reticulum calcium ion transport;cellular response to caffeine;cellular response to epinephrine stimulus;establishment of protein localization to endoplasmic reticulum;ventricular cardiac muscle cell action potential;Purkinje myocyte to ventricular cardiac muscle cell signaling;cell communication by electrical coupling involved in cardiac conduction;type B pancreatic cell apoptotic process;positive regulation of the force of heart contraction;regulation of AV node cell action potential;regulation of SA node cell action potential;regulation of atrial cardiac muscle cell action potential;regulation of ventricular cardiac muscle cell action potential;positive regulation of calcium-transporting ATPase activity;regulation of cardiac conduction
• Cellular component: smooth endoplasmic reticulum;plasma membrane;junctional sarcoplasmic reticulum membrane;membrane;sarcoplasmic reticulum;Z disc;cytoplasmic vesicle membrane;protein-containing complex;sarcoplasmic reticulum membrane;calcium channel complex;sarcolemma
• Molecular function: ryanodine-sensitive calcium-release channel activity;calcium channel activity;calcium ion binding;protein binding;calmodulin binding;calcium-release channel activity;enzyme binding;protein kinase A catalytic subunit binding;protein kinase A regulatory subunit binding;identical protein binding;protein self-association;suramin binding;ion channel binding;calcium-induced calcium release activity