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): 1:237042184-237833988
Previous symbols: [ "ARVD2" ]
Links
Phenotypes
GenCC
Source:
- 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:
| 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
- 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 | 3477 | |
| nonsense | 82 | 86 | ||||
| start loss | 1 | |||||
| frameshift | 79 | 85 | ||||
| inframe indel | 47 | 53 | ||||
| splice donor/acceptor (+/-2bp) | 70 | 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:
| 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:
- 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
- essential_gene_gene_trap
- 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