RYR1
ryanodine receptor 1, the group of Ryanodine receptors|Protein phosphatase 1 regulatory subunits
Basic information
Region (hg38): 19:38433690-38595273
Previous symbols: [ "MHS", "MHS1", "CCO" ]
Links
Phenotypes
GenCC
Source:
- congenital multicore myopathy with external ophthalmoplegia (Definitive), mode of inheritance: AR
- central core myopathy (Strong), mode of inheritance: AD
- malignant hyperthermia, susceptibility to, 1 (Strong), mode of inheritance: AD
- central core myopathy (Strong), mode of inheritance: AR
- congenital multicore myopathy with external ophthalmoplegia (Strong), mode of inheritance: AR
- central core myopathy (Supportive), mode of inheritance: AD
- malignant hyperthermia of anesthesia (Supportive), mode of inheritance: AD
- lethal multiple pterygium syndrome (Supportive), mode of inheritance: AR
- King-Denborough syndrome (Supportive), mode of inheritance: AD
- autosomal recessive centronuclear myopathy (Supportive), mode of inheritance: AR
- benign Samaritan congenital myopathy (Supportive), mode of inheritance: AR
- congenital myopathy with myasthenic-like onset (Supportive), mode of inheritance: AR
- malignant hyperthermia, susceptibility to, 1 (Definitive), mode of inheritance: AD
- central core myopathy (Strong), mode of inheritance: AD
- malignant hyperthermia, susceptibility to, 1 (Strong), mode of inheritance: AD
- central core myopathy (Strong), mode of inheritance: AR
- malignant hyperthermia, susceptibility to, 1 (Definitive), mode of inheritance: AD
- RYR1-related myopathy (Definitive), mode of inheritance: AR
- RYR1-related myopathy (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Malignant hyperthermia, susceptibility 1; King-Denborough syndrome; Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia; Congenital myopathy 1B, autosomal recessive; Centronuclear myopathy | AD/AR | Cardiovascular; Musculoskeletal; Renal; Pharmacogenomic | Individuals with recessive inheritance have been described; Invididuals are susceptible to malignant hyperthermic crisis (which can affect both skeletal muscle and cardiac function) in a number of situations, including when exposed to specific agents such as certain agents used in anesthesia (eg, halothane) or depolarizing muscle relaxants (eg, succinyl choline), and to treat or prevent acute crises, dantrolene can be effective; Individuals may also suffer from exertional rhabdomyolysis or have attacks triggered by tachycardia or acidosis, and precautions may be beneficial; For Minicore myopathy with external ophthalmoplegia, Centronuclear myopathy, individuals with these conditions may also be at risk of malignant hyperthermia, and appropriate precautions may be beneficial | Cardiovascular; Craniofacial; Musculoskeletal; Renal | 13396066; 637752; 7362206; 7299413; 6348539; 1774074; 8220423; 8220422; 9199552; 9497245; 10097181; 11113224; 11389482; 11448278; 12112081; 12136074; 12467748; 12719381; 14732627; 16380615; 16163667; 16084090; 17190947; 17376685; 17538032; 18253926; 18765655; 19303294; 19734047; 19807743; 20301565; 20301325; 20839240 |
| Individuals with RYR1-related conditions may be at risk of malignant hyperthermia |
ClinVar
This is a list of variants' phenotypes submitted to
- RYR1-related disorder (234 variants)
- not provided (56 variants)
- Central core myopathy (14 variants)
- Malignant hyperthermia, susceptibility to, 1 (8 variants)
- Congenital multicore myopathy with external ophthalmoplegia (7 variants)
- Malignant hyperthermia of anesthesia (3 variants)
- Myopathy (3 variants)
- Arthrogryposis multiplex congenita;Fetal akinesia deformation sequence 1 (2 variants)
- RYR1-related myopathy (2 variants)
- Congenital myopathy with fiber type disproportion (2 variants)
- Myopathy, RYR1-associated (1 variants)
- Fetal akinesia deformation sequence 1;Arthrogryposis multiplex congenita (1 variants)
- King Denborough syndrome;Central core myopathy;Congenital multicore myopathy with external ophthalmoplegia;Malignant hyperthermia, susceptibility to, 1 (1 variants)
- Malignant hyperthermia, susceptibility to (1 variants)
- King Denborough syndrome (1 variants)
- Arthrogryposis multiplex congenita (1 variants)
- Autism spectrum disorder due to AUTS2 deficiency (1 variants)
- Abnormality of the musculature (1 variants)
- Congenital multicore myopathy with external ophthalmoplegia;Congenital myopathy with fiber type disproportion;Central core myopathy;Malignant hyperthermia, susceptibility to, 1;King Denborough syndrome (1 variants)
- Ptosis;Absence of the sacrum;History of neonatal hypotonia (1 variants)
- Congenital multicore myopathy with external ophthalmoplegia;Congenital myopathy with fiber type disproportion;King Denborough syndrome;Central core myopathy;Malignant hyperthermia, susceptibility to, 1 (1 variants)
- Malignant hyperthermia, susceptibility to, 1;Congenital multicore myopathy with external ophthalmoplegia;Congenital myopathy with fiber type disproportion;Central core myopathy;King Denborough syndrome (1 variants)
- King Denborough syndrome;Malignant hyperthermia, susceptibility to, 1;Central core myopathy;Congenital myopathy with fiber type disproportion;Congenital multicore myopathy with external ophthalmoplegia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the RYR1 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 | 59 | 1977 | 32 | 2070 | ||
| missense | 37 | 168 | 3317 | 36 | 19 | 3577 |
| nonsense | 99 | 19 | 13 | 131 | ||
| start loss | 1 | |||||
| frameshift | 125 | 62 | 24 | 212 | ||
| inframe indel | 114 | 120 | ||||
| splice donor/acceptor (+/-2bp) | 18 | 90 | 20 | 129 | ||
| splice region ? | 5 | 162 | 344 | 9 | 520 | |
| non coding ? | 53 | 1267 | 259 | 1581 | ||
| Total | 280 | 346 | 3601 | 3284 | 310 |
Highest pathogenic variant AF is 0.0000394
Variants in RYR1
This is a list of pathogenic ClinVar variants found in the RYR1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 19-38433712-G-A | Central core myopathy • Congenital multicore myopathy with external ophthalmoplegia • Malignant hyperthermia, susceptibility to, 1 | Uncertain significance (Jan 13, 2018) | ||
| 19-38433722-T-C | Neuromuscular disease, congenital, with uniform type 1 fiber • Central core myopathy • Congenital multicore myopathy with external ophthalmoplegia • Malignant hyperthermia, susceptibility to, 1 | Benign (Jun 28, 2018) | ||
| 19-38433728-C-T | Central core myopathy • Neuromuscular disease, congenital, with uniform type 1 fiber • Malignant hyperthermia, susceptibility to, 1 • Congenital multicore myopathy with external ophthalmoplegia | Benign/Likely benign (Jan 13, 2018) | ||
| 19-38433741-CCCCAGCCCGCCCCCAGCCCTCCCG-C | Likely benign (Feb 11, 2019) | |||
| 19-38433746-G-GC | Malignant hyperthermia of anesthesia • Neuromuscular disease, congenital, with uniform type 1 fiber • Multiminicore myopathy • Central core myopathy | Uncertain significance (Jun 14, 2016) | ||
| 19-38433756-A-C | Central core myopathy • Congenital multicore myopathy with external ophthalmoplegia • Malignant hyperthermia, susceptibility to, 1 • Neuromuscular disease, congenital, with uniform type 1 fiber • Malignant hyperthermia, susceptibility to, 1;Congenital multicore myopathy with external ophthalmoplegia;Congenital myopathy with fiber type disproportion;Central core myopathy;King Denborough syndrome | Uncertain significance (Dec 14, 2021) | ||
| 19-38433757-G-GC | Malignant hyperthermia of anesthesia • Multiminicore myopathy • Neuromuscular disease, congenital, with uniform type 1 fiber • Central core myopathy | Uncertain significance (Jun 14, 2016) | ||
| 19-38433761-T-C | Malignant hyperthermia, susceptibility to, 1 • Central core myopathy • Congenital multicore myopathy with external ophthalmoplegia | Uncertain significance (Jan 13, 2018) | ||
| 19-38433761-T-G | Neuromuscular disease, congenital, with uniform type 1 fiber • Malignant hyperthermia, susceptibility to, 1 • Central core myopathy • Congenital multicore myopathy with external ophthalmoplegia • Malignant hyperthermia, susceptibility to, 1;Congenital multicore myopathy with external ophthalmoplegia;Congenital myopathy with fiber type disproportion;Central core myopathy;King Denborough syndrome | Uncertain significance (Aug 16, 2021) | ||
| 19-38433765-G-C | Central core myopathy • Malignant hyperthermia, susceptibility to, 1 • Congenital multicore myopathy with external ophthalmoplegia | Uncertain significance (Jan 12, 2018) | ||
| 19-38433769-A-C | Central core myopathy • Malignant hyperthermia, susceptibility to, 1 • Congenital multicore myopathy with external ophthalmoplegia | Uncertain significance (Jan 12, 2018) | ||
| 19-38433793-C-G | not specified | Likely benign (-) | ||
| 19-38433799-C-T | Malignant hyperthermia, susceptibility to, 1 • Congenital multicore myopathy with external ophthalmoplegia | Uncertain significance (Jan 13, 2018) | ||
| 19-38433832-G-C | Uncertain significance (Aug 02, 2022) | |||
| 19-38433834-G-C | Neuromuscular disease, congenital, with uniform type 1 fiber • Malignant hyperthermia, susceptibility to, 1 • Congenital multicore myopathy with external ophthalmoplegia • Central core myopathy | Uncertain significance (Jan 13, 2018) | ||
| 19-38433850-A-G | RYR1-related disorder | Likely benign (Aug 22, 2022) | ||
| 19-38433850-A-AGAC | RYR1-related disorder | Uncertain significance (Jul 06, 2022) | ||
| 19-38433853-C-A | Malignant hyperthermia, susceptibility to, 1 • Congenital multicore myopathy with external ophthalmoplegia | Uncertain significance (Aug 15, 2023) | ||
| 19-38433862-G-A | Likely benign (Jul 18, 2018) | |||
| 19-38433863-T-C | RYR1-related disorder | Uncertain significance (Aug 18, 2023) | ||
| 19-38433864-TCC-CG | not provided (-) | |||
| 19-38433865-C-G | Malignant hyperthermia, susceptibility to, 1 | Uncertain significance (Aug 15, 2023) | ||
| 19-38433867-T-G | Malignant hyperthermia, susceptibility to, 1 • RYR1-related disorder | Likely pathogenic (Apr 07, 2023) | ||
| 19-38433869-C-A | RYR1-related disorder • Malignant hyperthermia, susceptibility to, 1 | Likely benign (Dec 13, 2023) | ||
| 19-38433869-C-T | Malignant hyperthermia, susceptibility to, 1 | Uncertain significance (Feb 24, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| RYR1 | protein_coding | protein_coding | ENST00000359596 | 106 | 153866 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.59e-29 | 1.00 | 125404 | 0 | 344 | 125748 | 0.00137 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.92 | 2698 | 2.99e+3 | 0.901 | 0.000218 | 32806 |
| Missense in Polyphen | 524 | 603.91 | 0.86768 | 6389 | ||
| Synonymous | -2.17 | 1365 | 1.27e+3 | 1.08 | 0.0000972 | 9980 |
| Loss of Function | 9.05 | 97 | 252 | 0.385 | 0.0000139 | 2847 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00236 | 0.00234 |
| Ashkenazi Jewish | 0.00428 | 0.00428 |
| East Asian | 0.000881 | 0.000870 |
| Finnish | 0.00107 | 0.00106 |
| European (Non-Finnish) | 0.00158 | 0.00156 |
| Middle Eastern | 0.000881 | 0.000870 |
| South Asian | 0.000393 | 0.000392 |
| Other | 0.00164 | 0.00163 |
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 muscle contraction following depolarization of T-tubules (PubMed:11741831, PubMed:16163667). Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm (PubMed:18268335). Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity). {ECO:0000250|UniProtKB:E9PZQ0, ECO:0000269|PubMed:18268335, ECO:0000305|PubMed:11741831, ECO:0000305|PubMed:16163667}.;
- Disease
- DISEASE: Malignant hyperthermia 1 (MHS1) [MIM:145600]: Autosomal dominant pharmacogenetic disorder of skeletal muscle and is one of the main causes of death due to anesthesia. In susceptible people, an MH episode can be triggered by all commonly used inhalational anesthetics such as halothane and by depolarizing muscle relaxants such as succinylcholine. The clinical features of the myopathy are hyperthermia, accelerated muscle metabolism, contractures, metabolic acidosis, tachycardia and death, if not treated with the postsynaptic muscle relaxant, dantrolene. Susceptibility to MH can be determined with the 'in vitro' contracture test (IVCT): observing the magnitude of contractures induced in strips of muscle tissue by caffeine alone and halothane alone. Patients with normal response are MH normal (MHN), those with abnormal response to caffeine alone or halothane alone are MH equivocal (MHE(C) and MHE(H) respectively). {ECO:0000269|PubMed:10051009, ECO:0000269|PubMed:10484775, ECO:0000269|PubMed:10612851, ECO:0000269|PubMed:10823104, ECO:0000269|PubMed:10888602, ECO:0000269|PubMed:11241852, ECO:0000269|PubMed:11389482, ECO:0000269|PubMed:11525881, ECO:0000269|PubMed:11575529, ECO:0000269|PubMed:11928716, ECO:0000269|PubMed:12059893, ECO:0000269|PubMed:12066726, ECO:0000269|PubMed:12123492, ECO:0000269|PubMed:12208234, ECO:0000269|PubMed:12411788, ECO:0000269|PubMed:12709367, ECO:0000269|PubMed:12883402, ECO:0000269|PubMed:1354642, ECO:0000269|PubMed:14732627, ECO:0000269|PubMed:14985404, ECO:0000269|PubMed:15221887, ECO:0000269|PubMed:15448513, ECO:0000269|PubMed:16163667, ECO:0000269|PubMed:1774074, ECO:0000269|PubMed:19191329, ECO:0000269|PubMed:19685112, ECO:0000269|PubMed:20142353, ECO:0000269|PubMed:20681998, ECO:0000269|PubMed:23558838, ECO:0000269|PubMed:24013571, ECO:0000269|PubMed:26115329, ECO:0000269|PubMed:26381711, ECO:0000269|PubMed:26631338, ECO:0000269|PubMed:27586648, ECO:0000269|PubMed:7751854, ECO:0000269|PubMed:7849712, ECO:0000269|PubMed:7881417, ECO:0000269|PubMed:8012359, ECO:0000269|PubMed:8220423, ECO:0000269|PubMed:9066328, ECO:0000269|PubMed:9138151, ECO:0000269|PubMed:9389851, ECO:0000269|PubMed:9450902, ECO:0000269|PubMed:9497245}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Central core disease of muscle (CCD) [MIM:117000]: Autosomal dominant congenital myopathy, but a severe autosomal recessive form also exists. Both clinical and histological variability is observed. Affected individuals typically display hypotonia and proximal muscle weakness in infancy, leading to the delay of motor milestones. The clinical course of the disorder is usually slow or nonprogressive in adulthood, and the severity of the symptoms may vary from normal to significant muscle weakness. Microscopic examination of CCD-affected skeletal muscle reveals a predominance of type I fibers containing amorphous-looking areas (cores) that do not stain with oxidative and phosphorylase histochemical techniques. {ECO:0000269|PubMed:10097181, ECO:0000269|PubMed:11113224, ECO:0000269|PubMed:11709545, ECO:0000269|PubMed:11741831, ECO:0000269|PubMed:12112081, ECO:0000269|PubMed:12136074, ECO:0000269|PubMed:12565913, ECO:0000269|PubMed:12566385, ECO:0000269|PubMed:12937085, ECO:0000269|PubMed:14670767, ECO:0000269|PubMed:14985404, ECO:0000269|PubMed:17204054, ECO:0000269|PubMed:17226826, ECO:0000269|PubMed:18253926, ECO:0000269|PubMed:18312400, ECO:0000269|PubMed:20142353, ECO:0000269|PubMed:21674524, ECO:0000269|PubMed:23558838, ECO:0000269|PubMed:24561095, ECO:0000269|PubMed:26381711, ECO:0000269|PubMed:27234031, ECO:0000269|PubMed:27586648, ECO:0000269|PubMed:7829078, ECO:0000269|PubMed:8220422, ECO:0000269|PubMed:8220423, ECO:0000269|PubMed:9497245}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiminicore disease with external ophthalmoplegia (MMDO) [MIM:255320]: Clinically heterogeneous neuromuscular disorder. General features include neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable. Muscle biopsy shows multiple, poorly circumscribed, short areas of sarcomere disorganization and mitochondria depletion (areas termed minicores) in most muscle fibers. Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present in multiminicore disease. {ECO:0000269|PubMed:12719381, ECO:0000269|PubMed:16380615, ECO:0000269|PubMed:20583297}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in RYR1 may be a cause of Samaritan myopathy, a congenital myopathy with benign course. Patients display severe hypotonia and respiratory distress at birth. Unlike other congenital myopathies, the health status constantly improves and patients are minimally affected at adulthood.;
- Pathway
- Oxytocin signaling pathway - Homo sapiens (human);Long-term depression - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Myometrial Relaxation and Contraction Pathways;Cell-type Dependent Selectivity of CCK2R Signaling;Calcium Regulation in the Cardiac Cell;Stimuli-sensing channels;Ion channel transport;Ion homeostasis;Transport of small molecules;Cardiac conduction;Muscle contraction
(Consensus)
Intolerance Scores
- loftool
- 0.00248
- rvis_EVS
- -8.29
- rvis_percentile_EVS
- 0.01
Haploinsufficiency Scores
- pHI
- 0.222
- hipred
- Y
- hipred_score
- 0.637
- ghis
- 0.539
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.872
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Ryr1
- Phenotype
- muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); digestive/alimentary phenotype; limbs/digits/tail phenotype; skeleton phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); 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);
Zebrafish Information Network
- Gene name
- ryr1b
- Affected structure
- fast muscle cell
- Phenotype tag
- abnormal
- Phenotype quality
- disorganized
Gene ontology
- Biological process
- response to hypoxia;outflow tract morphogenesis;calcium ion transport;muscle contraction;release of sequestered calcium ion into cytosol by sarcoplasmic reticulum;response to caffeine;ion transmembrane transport;skin development;ossification involved in bone maturation;skeletal muscle fiber development;release of sequestered calcium ion into cytosol;protein homotetramerization;regulation of cytosolic calcium ion concentration;cellular response to calcium ion;cellular response to caffeine;regulation of cardiac conduction
- Cellular component
- cytoplasm;smooth endoplasmic reticulum;plasma membrane;integral component of plasma membrane;cell cortex;junctional sarcoplasmic reticulum membrane;terminal cisterna;sarcoplasmic reticulum;Z disc;junctional membrane complex;T-tubule;cytoplasmic vesicle membrane;integral component of organelle membrane;I band;sarcoplasmic reticulum membrane;calcium channel complex;sarcolemma;extracellular exosome;ryanodine receptor complex
- Molecular function
- protease binding;ryanodine-sensitive calcium-release channel activity;voltage-gated calcium channel activity;calcium channel activity;calcium ion binding;protein binding;calmodulin binding;ATP binding;calcium-release channel activity;calcium-induced calcium release activity