RYR1

ryanodine receptor 1, the group of Ryanodine receptors|Protein phosphatase 1 regulatory subunits

Basic information

Region (hg38): 19:38433691-38595273

Previous symbols: [ "MHS", "MHS1", "CCO" ]

Links

ENSG00000196218 ∙ NCBI:6261 ∙ OMIM:180901 ∙ HGNC:10483 ∙ Uniprot:P21817 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the RYR1 gene.

• RYR1-related_disorder (7033 variants)
• Malignant_hyperthermia,_susceptibility_to,_1 (4043 variants)
• not_provided (2779 variants)
• Central_core_myopathy (1108 variants)
• Congenital_multicore_myopathy_with_external_ophthalmoplegia (976 variants)
• not_specified (661 variants)
• King_Denborough_syndrome (572 variants)
• Congenital_myopathy_with_fiber_type_disproportion (531 variants)
• Inborn_genetic_diseases (491 variants)
• Neuromuscular_disease,_congenital,_with_uniform_type_1_fiber (271 variants)
• Malignant_hyperthermia_of_anesthesia (232 variants)
• RYR1-related_myopathy (95 variants)
• Multiminicore_myopathy (68 variants)
• enflurane_response_-_Toxicity (38 variants)
• desflurane_response_-_Toxicity (38 variants)
• sevoflurane_response_-_Toxicity (38 variants)
• isoflurane_response_-_Toxicity (38 variants)
• succinylcholine_response_-_Toxicity (38 variants)
• methoxyflurane_response_-_Toxicity (38 variants)
• halothane_response_-_Toxicity (38 variants)
• Centronuclear_myopathy (37 variants)
• Myopathy,_RYR1-associated (15 variants)
• Malignant_hypothermia (13 variants)
• Arthrogryposis_multiplex_congenita (13 variants)
• Congenital_myopathy (12 variants)
• See_cases (11 variants)
• Fetal_akinesia_deformation_sequence_1 (11 variants)
• Myopathy (11 variants)
• Abnormality_of_the_musculature (8 variants)
• Neuromuscular_disease (6 variants)
• Limb-girdle_muscular_dystrophy (5 variants)
• Long_QT_syndrome (4 variants)
• Congenital_muscular_dystrophy (4 variants)
• Autosomal_dominant_centronuclear_myopathy (3 variants)
• Exercise-induced_myalgia (3 variants)
• Delayed_gross_motor_development (3 variants)
• Myalgia (3 variants)
• Elevated_circulating_creatine_kinase_concentration (3 variants)
• Central_core_disease,_autosomal_recessive (3 variants)
• EMG:_myopathic_abnormalities (2 variants)
• Scoliosis (2 variants)
• Respiratory_insufficiency (2 variants)
• Malignant_hyperthermia_and_exertional_rhabdomyolosis (2 variants)
• Hereditary_skeletal_muscle_disorder (2 variants)
• Generalized_muscle_weakness (2 variants)
• Hydrops_fetalis (2 variants)
• Pelvic_girdle_muscle_weakness (2 variants)
• Progressive_distal_muscle_weakness (2 variants)
• Epilepsy (2 variants)
• Malignant_hyperthermia,_susceptibility_to (2 variants)
• Axial_myopathy,_late-onset (2 variants)
• Distal_arthrogryposis (2 variants)
• Proximal_muscle_weakness (2 variants)
• Congenital_hip_dislocation (2 variants)
• Congenital_myasthenic_syndrome (2 variants)
• Distal_myopathy (1 variants)
• Clubfoot (1 variants)
• Osteoporosis (1 variants)
• Muscular_dystrophy_and_arthrogryposis (1 variants)
• Autism_spectrum_disorder_due_to_AUTS2_deficiency (1 variants)
• Muscle_tissue_disorder (1 variants)
• Anterior_segment_dysgenesis_7 (1 variants)
• Myopathy,_progressive_axial_with_cataracts (1 variants)
• Malignant_hyperthermia_equivocal_with_halotane (1 variants)
• Ptosis (1 variants)
• Proximal_amyotrophy (1 variants)
• Short_stature (1 variants)
• Congenital_myasthenic_syndrome_12 (1 variants)
• Congenital_myopathy_with_cores (1 variants)
• EMG_abnormality (1 variants)
• Rhabdomyolysis (1 variants)
• Intellectual_disability (1 variants)
• Absence_of_the_sacrum (1 variants)
• Mildly_elevated_creatine_kinase (1 variants)
• Hypotonia (1 variants)
• Multiminicore/minicore/multicore_disease (1 variants)
• Lower_limb_amyotrophy (1 variants)
• History_of_neonatal_hypotonia (1 variants)
• Limb_pain (1 variants)
• Arrhythmogenic_right_ventricular_cardiomyopathy (1 variants)
• Lynch_syndrome_5 (1 variants)
• Myotonia (1 variants)
• Multi-minicore_disease_and_atypical_periodic_paralysis (1 variants)
• Rhabdomyolysis-myalgia_syndrome (1 variants)
• Congenital_contracture (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. These statistics are base on transcript: NM_000000540.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	6	95	2375	16	2494
missense	76	318	4010	107	20	4531
nonsense	106	45	20			171
start loss			1			1
frameshift	149	103	44	1		297
splice donor/acceptor (+/-2bp)	22	133	23	3		181
Total	355	605	4193	2486	36

Highest pathogenic variant AF is 0.00021201343

GnomAD

Source: gnomAD

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: 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 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