RYR1

Summary

RYR1 (ryanodine receptor 1, HGNC:10483) is a protein-coding gene on chromosome 19q13.2, encoding Ryanodine receptor 1 (P21817). 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 muscle contraction following depolarization of T-tubules.

This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described.

Source: NCBI Gene 6261 — RefSeq curated summary.

At a glance

• Gene–disease (curated): malignant hyperthermia, susceptibility to, 1 (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 10,759 total — 340 pathogenic, 334 likely-pathogenic
• Phenotypes (HPO): 223
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000540

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10483
Approved symbol	RYR1
Name	ryanodine receptor 1
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	RYR, PPP1R137
Ensembl gene	ENSG00000196218
Ensembl biotype	protein_coding
OMIM	180901
Entrez	6261

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 5 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000355481, ENST00000359596, ENST00000593322, ENST00000594111, ENST00000594335, ENST00000596431, ENST00000599547, ENST00000600337, ENST00000601514, ENST00000688602, ENST00000689936, ENST00000692547, ENST00000713952, ENST00000713953

RefSeq mRNA: 2 — MANE Select: NM_000540 NM_000540, NM_001042723

CCDS: CCDS33011, CCDS42563

Canonical transcript exons

ENST00000359596 — 106 exons

Exon	Start	End
ENSE00000368631	38567773	38567917
ENSE00000368639	38580370	38580504
ENSE00000780393	38586091	38586191
ENSE00000780396	38585938	38586002
ENSE00000780398	38579982	38580128
ENSE00000780399	38578144	38578204
ENSE00000780400	38577918	38578048
ENSE00000780406	38566911	38566987
ENSE00000780407	38564959	38565771
ENSE00000826242	38572019	38572270
ENSE00000826243	38570607	38570693
ENSE00001749062	38573177	38573307
ENSE00001752702	38584943	38585099
ENSE00001793829	38586525	38586576
ENSE00002278946	38575919	38575961
ENSE00003518437	38546445	38546526
ENSE00003576440	38561113	38561454
ENSE00003590641	38548233	38548420
ENSE00003590781	38543532	38543660
ENSE00003596210	38543771	38543875
ENSE00003649416	38537880	38537960
ENSE00003663907	38543347	38543435
ENSE00003935766	38587325	38587564
ENSE00004021898	38443718	38443796
ENSE00004021899	38510498	38510565
ENSE00004021900	38477710	38477870
ENSE00004021901	38535316	38535392
ENSE00004021902	38483290	38483516
ENSE00004021903	38492490	38492636
ENSE00004021904	38469305	38469513
ENSE00004021905	38443558	38443632
ENSE00004021906	38532671	38532736
ENSE00004021907	38500821	38500990
ENSE00004021908	38506303	38506377
ENSE00004021909	38532490	38532541
ENSE00004021910	38504748	38504911
ENSE00004021911	38475318	38475450
ENSE00004021912	38528599	38528695
ENSE00004021913	38504220	38504360
ENSE00004021916	38463747	38463850
ENSE00004021918	38494352	38494625
ENSE00004021919	38466091	38466398
ENSE00004021921	38534720	38534819
ENSE00004021922	38510660	38510781
ENSE00004021923	38506471	38506546
ENSE00004021924	38444149	38444261
ENSE00004021925	38523217	38523309
ENSE00004021926	38455451	38455546
ENSE00004021928	38507712	38507827
ENSE00004021929	38433691	38433874
ENSE00004021930	38499108	38499243
ENSE00004021931	38440745	38440864
ENSE00004021932	38468966	38469140
ENSE00004021933	38489177	38489443
ENSE00004021934	38446472	38446565
ENSE00004021935	38496860	38496954
ENSE00004021936	38499908	38500016
ENSE00004021937	38496409	38496541
ENSE00004021938	38506829	38506952
ENSE00004021939	38473377	38473771
ENSE00004021940	38448355	38448511
ENSE00004021941	38459146	38459338
ENSE00004021942	38523915	38523929
ENSE00004021943	38502880	38502970
ENSE00004021944	38526993	38527052
ENSE00004021945	38523028	38523115
ENSE00004021946	38467610	38467812
ENSE00004021947	38525332	38525502
ENSE00004021948	38528951	38529057
ENSE00004021949	38512245	38512483
ENSE00004021950	38478435	38478600
ENSE00004021951	38496215	38496329
ENSE00004021952	38490076	38490276
ENSE00004021953	38455633	38455751
ENSE00004021954	38499635	38499821
ENSE00004021956	38448649	38448813
ENSE00004021957	38527647	38527784
ENSE00004021958	38460375	38460591
ENSE00004021959	38490621	38490732
ENSE00004021960	38505003	38505081
ENSE00004021961	38528306	38528418
ENSE00004021962	38444584	38444677
ENSE00004021963	38451764	38451885
ENSE00004021964	38483027	38483113
ENSE00004021965	38463423	38463527
ENSE00004021966	38515026	38515107
ENSE00004021967	38485590	38486202
ENSE00004021968	38458051	38458292
ENSE00004021969	38511561	38511610
ENSE00004021970	38452819	38453014
ENSE00004021971	38517359	38517691
ENSE00004021972	38500606	38500726
ENSE00004021973	38519214	38519454
ENSE00004021974	38512072	38512132
ENSE00004021975	38535997	38536070
ENSE00004021977	38536750	38536767
ENSE00004021978	38505309	38505398
ENSE00004021979	38516087	38516217
ENSE00004021980	38464639	38464722
ENSE00004021982	38442349	38442453
ENSE00004021983	38535141	38535220
ENSE00004021984	38502507	38502727
ENSE00004021985	38446694	38446768
ENSE00004021986	38455235	38455370
ENSE00004021987	38505806	38505946
ENSE00004021988	38457497	38457630

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 99.63.

FANTOM5 (CAGE): breadth broad, TPM avg 6.1775 / max 1164.4710, expressed in 456 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175635	5.5988	433
175634	0.3747	155
175633	0.1710	79
175639	0.0330	16

Top tissues by expression

278 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	99.63	gold quality
gastrocnemius	UBERON:0001388	99.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.32	gold quality
triceps brachii	UBERON:0001509	99.26	gold quality
vastus lateralis	UBERON:0001379	99.25	gold quality
quadriceps femoris	UBERON:0001377	99.24	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.24	gold quality
skeletal muscle tissue	UBERON:0001134	99.04	gold quality
tibialis anterior	UBERON:0001385	98.99	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.79	gold quality
biceps brachii	UBERON:0001507	98.40	gold quality
muscle organ	UBERON:0001630	98.29	gold quality
deltoid	UBERON:0001476	98.23	gold quality
diaphragm	UBERON:0001103	98.13	gold quality
muscle of leg	UBERON:0001383	97.98	gold quality
body of tongue	UBERON:0011876	97.49	gold quality
muscle tissue	UBERON:0002385	92.00	gold quality
sural nerve	UBERON:0015488	89.93	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.24	gold quality
tongue	UBERON:0001723	86.60	gold quality
right frontal lobe	UBERON:0002810	86.40	gold quality
cerebellar hemisphere	UBERON:0002245	86.24	gold quality
cerebellar cortex	UBERON:0002129	86.07	gold quality
amygdala	UBERON:0001876	85.75	gold quality
cingulate cortex	UBERON:0003027	85.62	gold quality
hypothalamus	UBERON:0001898	85.61	gold quality
anterior cingulate cortex	UBERON:0009835	85.55	gold quality
caudate nucleus	UBERON:0001873	85.25	gold quality
cerebellum	UBERON:0002037	84.09	gold quality
left testis	UBERON:0004533	83.84	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting RYR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-4640-5P	97.42	66.33	1543
HSA-MIR-4712-5P	97.24	67.79	775
HSA-MIR-770-5P	97.24	68.10	758
HSA-MIR-4726-5P	97.24	65.67	1299
HSA-MIR-6085	96.57	64.11	621
HSA-MIR-4652-5P	96.46	64.22	553
HSA-MIR-6813-5P	94.68	64.20	588

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• genotype-phenotype comparison of the Swiss malignant hyperthermia population (PMID:11668625)
• The mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of ryanodine receptor (RYR1). (PMID:11709545)
• point mutations in the RYR1 gene are strongly associated with the MH phenotype (PMID:12059893)
• Malignant hyperthermia associated with exercise-induced rhabdomyolysis, congenital abnormalities and a novel RYR1 mutation in New Zealand and Australian pedigrees. (PMID:12066726)
• Results describe a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. (PMID:12112081)
• RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test (IVCT) phenotypes. (PMID:12124989)
• Congenital myopathy appears to be associated with recessive RYR1 mutations. (PMID:12136074)
• Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. (PMID:12565913)
• The same haplotype was shown to segregate with the individuals carrying the Arg614Cys mutation in chromosome 19; however, the other susceptible and equivocal individuals do not share this haplotype. (PMID:14500992)
• findings indicate a novel negative feedback mechanism between RyR1 channel activity and CD38 abundance acts in cADPr signal transduction in lymphoma b-cells (PMID:14596927)
• RyR1 Ile2182Phe and Gly2375Ala mutations are pathogenic for malignant hyperthermia (PMID:14641996)
• there is a specific binding subdomain in RyR1 and RyR2 participating in RyR-RyR interaction (PMID:14722100)
• DNA mutational analysis in central core disease patients in the UK (PMID:14985404)
• The r401C substitution in the RYR1 geneis associated with this adult onset multi/minicore myopathy. (PMID:14999498)
• This is the 1st evidence that RyRs directly control primary beta cell insulin secretion independently of glucose & by 2 mechanisms, including a novel cytosolic Ca2+-independent mechanism likely involving changes in Ca2+ in the lumens of non-ER organelles. (PMID:15033925)
• The presence of RyR1 mutations with impact on calcium homeostasis emphasizes the functional significance of exon 44. (PMID:15210166)
• role of the sequence surrounding M4 in ryanodine receptors in membrane association and function was investigated (PMID:15226293)
• RYR1 enhances the production of the inflammatory cytokine IL-6, which may in turn affect signaling pathways responsible for the trophic status of muscle fibers. (PMID:15299003)
• Patients with RYR1-related congenital myopathies have a recognizable pattern of muscle involvement irrespective of the variability of associated histopathological findings. (PMID:15564033)
• analysis of skeletal muscle cells expressing recombinant ryanodine receptors with malignant hyperthermia and central core disease mutations (PMID:15689621)
• the Ca2+ release channel sensitive to NAADP in T-lymphocytes is the ryanodine receptor (PMID:15774471)
• We suggest that aberrant splicing of RyR1 mRNAs might contribute to impaired Ca2+ homeostasis in DM1 muscle (PMID:15972723)
• Mutations in the ryanodine receptor gene might affect the function of this intracellular calcium release channel and lead to neuromuscular disorders. (PMID:16084090)
• in addition to negatively charged residues on the lumenal side, rings of four negative charges formed by D4938 and D4945 in the cytosolic vestibule determine RyR ion fluxes (PMID:16239337)
• The development of a heterozygous mouse model of the Y522S RyR1 mutation, including their susceptibility to heat and anesthetic-induced malignant hyperthermia, is reported. (PMID:16284304)
• functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-minicore disease (PMID:16372898)
• Recessive mutations of RYR1 domains are prevalent in multi-minicore disease with external ophthalmoplegia, suggesting a different pathomechanism from that of central core disease. (PMID:16380615)
• expression of TRPC3 is tightly regulated during muscle cell differentiation and functional interaction between TRPC3 and RyR1 may regulate the gain of SR Ca(2+) release independent of SR Ca(2+) load (PMID:16484216)
• 16 novel mutations are associated with susceptibility to malignant hyperthermia. (PMID:16835904)
• The RYR1 p.Val4927_Ile4928del deletion reduces Ca(2+) release by disrupting Ca(2+) gating and eliminating Ca(2+) permeation through the open channel. (PMID:16958053)
• RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and this unveils recessive mutations in patients with core myopathies. (PMID:17033962)
• A discrete subset of cysteines is likely to be involved in the functional response of type-1 ryanodine receptor to different redox modifications (S-nitrosylation, S-glutathionylation, and oxidation to disulfides). (PMID:17071618)
• Our data suggest genetic heterogeneity in autosomal dominant core myopathies and the existence of additional unidentified genes. (PMID:17190947)
• study shows that recessive inheritance in central core disease may be more common than previously appreciated (PMID:17226826)
• together, our results demonstrate that RyR1 differs markedly from RyR2 with respect to their responses to Ca(2+) overload and luminal Ca(2+). (PMID:17259277)
• Altered tetramer assembly/stability coupled with subtle chronic changes in Ca2+ homoeostasis over the long term may contribute to the development of core lesions and incomplete malignant hyperthermia susceptibility. (PMID:17293538)
• Phenotypical spectrum associated with RYR1 mutations and indicate that RYR1 screening should be considered in centronuclear myopathy (PMID:17376685)
• Four of 10 patients had a heterozygous mutation, three missense and one deletion, all in the C-terminal domain of RYR1. (PMID:17538032)
• Data showed for the first time that human dendritic cells preferentially express RyR1 mRNA among RyR isoforms. (PMID:17707769)
• The cardiac ryanodine receptor mutations linked to cardiac arrhythmia and sudden death alter the threshold for store-overload-induced Ca2+ release. (PMID:18092949)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ryr1a	ENSDARG00000011422
danio_rerio	ryr1b	ENSDARG00000023797
mus_musculus	Ryr1	ENSMUSG00000030592
rattus_norvegicus	Ryr1	ENSRNOG00000020557
drosophila_melanogaster	RyR	FBGN0011286
caenorhabditis_elegans		WBGENE00006801

Paralogs (5): ITPR3 (ENSG00000096433), ITPR2 (ENSG00000123104), ITPR1 (ENSG00000150995), RYR2 (ENSG00000198626), RYR3 (ENSG00000198838)

Protein

Protein identifiers

Ryanodine receptor 1 — P21817 (reviewed: P21817)

Alternative names: Skeletal muscle calcium release channel, Skeletal muscle ryanodine receptor, Skeletal muscle-type ryanodine receptor, Type 1 ryanodine receptor

All UniProt accessions (8): A0A8I5KSR1, A0A8I5KUY6, A0AAQ5BH72, A0AAQ5BH76, P21817, M0R014, M0R0S0, M0R127

UniProt curated annotations — full annotation on UniProt →

Function. 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 muscle contraction following depolarization of T-tubules. Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm. 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.

Subunit / interactions. Homotetramer. Can also form heterotetramers with RYR2. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1). Repeated very high-level exercise decreases interaction with PDE4D and protein phosphatase 1 (PP1). Interacts with CALM; CALM with bound calcium inhibits the RYR1 channel activity. Interacts with S100A1. Interacts with FKBP1A; this stabilizes the closed conformation of the channel. Interacts with CACNA1S; interaction with CACNA1S is important for activation of the RYR1 channel. Interacts with CACNB1. Interacts with TRDN and ASPH; these interactions stimulate RYR1 channel activity. Interacts with SELENON. Interacts with scorpion calcins (AC P0DPT1; AC P0DM30; AC A0A1L4BJ42; AC P59868; AC P60254; AC B8QG00; AC L0GBR1; AC P60252; AC P60253).

Subcellular location. Sarcoplasmic reticulum membrane.

Tissue specificity. Skeletal muscle and brain (cerebellum and hippocampus).

Post-translational modifications. Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843. Activated by reversible S-nitrosylation. Repeated very high-level exercise increases S-nitrosylation.

Disease relevance. 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). Disease susceptibility is associated with variants affecting the gene represented in this entry. Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia (CMYO1A) [MIM:117000] An autosomal dominant myopathy characterized by hypotonia and proximal muscle weakness primarily affecting the lower limbs, beginning in infancy or early childhood. Some patients manifest later onset of symptoms. The clinical course of the disorder is usually slow or non-progressive in adulthood, and the severity of the symptoms is variable. Affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Microscopic examination of 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. Additional pathologic findings may also be observed on muscle biopsy. CMYO1A affected individuals are at risk for malignant hyperthermia, and both disorders may be present in the same family. The disease is caused by variants affecting the gene represented in this entry. Congenital myopathy 1B, autosomal recessive (CMYO1B) [MIM:255320] An autosomal recessive myopathy characterized by severe hypotonia and generalized muscle weakness and atrophy apparent soon after birth or in early childhood. Affected individuals show delayed motor development, proximal muscle weakness with axial and shoulder girdle involvement, difficulty walking or running, external ophthalmoplegia, and bulbar weakness often resulting in feeding difficulties and respiratory insufficiency. Disease severity is variable. Some affected individuals show symptoms in utero, including reduced fetal movements, polyhydramnios, and intrauterine growth restriction. Some patients have lethal fetal akinesia with death in utero. Muscle biopsy can show variable findings, including multiple and poorly circumscribed areas of sarcomere disorganization and mitochondria depletion (areas termed minicores). Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present. The disease is caused by variants affecting the gene represented in this entry. 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. King-Denborough syndrome (KDS) [MIM:619542] An autosomal dominant disorder characterized by the triad of dysmorphic features, congenital myopathy, and susceptibility to malignant hyperthermia. Variable expressivity has been reported in several cases. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The calcium release is activated by increased cytosolic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites.

Domain organisation. The calcium release channel activity resides in the C-terminal region while the remaining part of the protein constitutes the ‘foot’ structure spanning the junctional gap between the sarcoplasmic reticulum (SR) and the T-tubule. Pore opening is mediated via the cytoplasmic calcium-binding domains that mediate a small rotation of the channel-forming transmembrane regions that then leads to channel opening.

Miscellaneous. Coexpression of normal and mutant Thr-4898 RYR1 in a 1:1 ratio produces RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release are reduced by 67%. Binding of [3H]ryanodine indicates that the heterozygous channel is activated by Ca(2+) concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells shows a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. Comparison with 2 other coexpressed mutant/normal channels suggests that the Thr-4898 mutation produces one of the most abnormal RYR1 channels that has been investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected CCD individuals.

Similarity. Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR1 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P21817-1	1	yes
P21817-2	2
P21817-3	3

RefSeq proteins (2): NP_000531, NP_001036188 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000699	RIH_dom	Domain
IPR001870	B30.2/SPRY	Domain
IPR003032	Ryanodine_rcpt	Domain
IPR003877	SPRY_dom	Domain
IPR005821	Ion_trans_dom	Domain
IPR009460	Ryanrecept_TM4-6	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013333	Ryan_recept	Family
IPR013662	RIH_assoc-dom	Domain
IPR014821	Ins145_P3_rcpt	Domain
IPR015925	Ryanodine_IP3_receptor	Family
IPR016093	MIR_motif	Domain
IPR035761	SPRY1_RyR	Domain
IPR035762	SPRY3_RyR	Domain
IPR035764	SPRY2_RyR	Domain
IPR035910	RyR/IP3R_RIH_dom_sf	Homologous_superfamily
IPR036300	MIR_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR048581	RYDR_Jsol	Domain

Pfam: PF00520, PF00622, PF01365, PF02026, PF02815, PF06459, PF08454, PF08709, PF21119

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (286 total): sequence variant 204, region of interest 11, compositionally biased region 10, domain 9, topological domain 8, modified residue 8, binding site 7, transmembrane region 6, repeat 6, sequence conflict 4, mutagenesis site 3, helix 3, splice variant 2, chain 1, intramembrane region 1, turn 1, strand 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6UHS	X-RAY DIFFRACTION	2.46
6UHI	X-RAY DIFFRACTION	2.88

Predicted structure (AlphaFold)

No AlphaFold model available for P21817 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 3892; 3966; 4210–4214; 4717; 4955–4960; 4980–4986; 5002

Post-translational modifications (8): 1337, 2345, 2843, 3635, 4467, 4471, 4864, 4867

Mutagenesis-validated functional residues (3):

Position	Phenotype
522	increases calcium-induced calcium release activity.
2508	increases sensitivity to caffeine and 4-chloro-m-cresol.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-5578775	Ion homeostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction
R-HSA-983712	Ion channel transport

MSigDB gene sets: 677 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, RORA1_01, MODULE_64, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, DARWICHE_SKIN_TUMOR_PROMOTER_UP, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, MODULE_329, CAGCTG_AP4_Q5, MORF_RAD51L3

GO Biological Process (21): response to hypoxia (GO:0001666), outflow tract morphogenesis (GO:0003151), calcium ion transport (GO:0006816), muscle contraction (GO:0006936), striated muscle contraction (GO:0006941), release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808), response to caffeine (GO:0031000), skin development (GO:0043588), ossification involved in bone maturation (GO:0043931), skeletal muscle fiber development (GO:0048741), release of sequestered calcium ion into cytosol (GO:0051209), protein homotetramerization (GO:0051289), regulation of cytosolic calcium ion concentration (GO:0051480), cellular response to calcium ion (GO:0071277), cellular response to caffeine (GO:0071313), monoatomic ion transport (GO:0006811), intracellular calcium ion homeostasis (GO:0006874), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (12): ryanodine-sensitive calcium-release channel activity (GO:0005219), voltage-gated calcium channel activity (GO:0005245), calcium channel activity (GO:0005262), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), ATP binding (GO:0005524), intracellularly gated calcium channel activity (GO:0015278), calcium-induced calcium release activity (GO:0048763), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (16): cytoplasm (GO:0005737), smooth endoplasmic reticulum (GO:0005790), plasma membrane (GO:0005886), cell cortex (GO:0005938), junctional sarcoplasmic reticulum membrane (GO:0014701), terminal cisterna (GO:0014802), sarcoplasmic reticulum (GO:0016529), Z disc (GO:0030018), organelle membrane (GO:0031090), I band (GO:0031674), sarcoplasmic reticulum membrane (GO:0033017), calcium channel complex (GO:0034704), sarcolemma (GO:0042383), extracellular exosome (GO:0070062), ryanodine receptor complex (GO:1990425), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Ion channel transport	1
Cardiac conduction	1
Muscle contraction	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transport	2
endoplasmic reticulum	2
membrane	2
cell periphery	2
sarcoplasmic reticulum membrane	2
sarcoplasmic reticulum	2
response to stress	1
response to decreased oxygen levels	1
heart morphogenesis	1
anatomical structure morphogenesis	1
metal ion transport	1
muscle system process	1
muscle contraction	1
sarcoplasmic reticulum calcium ion transport	1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1
response to purine-containing compound	1
response to alkaloid	1
animal organ development	1
ossification	1
bone maturation	1
skeletal muscle tissue development	1
myotube cell development	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
protein homooligomerization	1
protein tetramerization	1
intracellular calcium ion homeostasis	1
response to calcium ion	1
cellular response to metal ion	1
response to caffeine	1
cellular response to alkaloid	1
cellular response to purine-containing compound	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
intracellular signaling cassette	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
calcium-induced calcium release activity	1

Protein interactions and networks

STRING

2104 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RYR1	FKBP1A	P20071	997
RYR1	CALML3	P27482	990
RYR1	CALML5	Q9NZT1	990
RYR1	CALML6	Q8TD86	989
RYR1	CALML4	Q96GE6	989
RYR1	QDPR	P09417	986
RYR1	CACNA1S	Q13698	986
RYR1	FKBP1B	P68106	981
RYR1	CALM1	P02593	979
RYR1	TRDN	Q13061	950
RYR1	JPH1	Q9HDC5	944
RYR1	ATP2A1	O14983	928
RYR1	STAC3	Q96MF2	854
RYR1	SELENON	Q9NZV5	847
RYR1	MTM1	Q13496	842

IntAct

21 interactions, top by confidence:

A	B	Type	Score
RACK1	RIOK3	psi-mi:“MI:0914”(association)	0.640
RYR1	MYOM2	psi-mi:“MI:2364”(proximity)	0.450
TERF1	RYR1	psi-mi:“MI:0407”(direct interaction)	0.440
RYR1	PPP1CA	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
PPP2CA	RYR1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
GRB2	RYR1	psi-mi:“MI:0915”(physical association)	0.400
NCK1	RYR1	psi-mi:“MI:0915”(physical association)	0.400
RYR1	PLCG1	psi-mi:“MI:0915”(physical association)	0.400
TF	IGKV2D-40	psi-mi:“MI:0914”(association)	0.350
RYR1	FKBP1A	psi-mi:“MI:0914”(association)	0.350
METTL3	TUBAL3	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ATG16L1		psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350
MYOM2	RYR1	psi-mi:“MI:0915”(physical association)	0.000
PDLIM3	RYR1	psi-mi:“MI:0915”(physical association)	0.000
RYR1	TTN	psi-mi:“MI:0915”(physical association)	0.000
RYR1	TULP3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (52): ANK1 (Reconstituted Complex), CALM1 (Far Western), RYR1 (FRET), RYR1 (Affinity Capture-MS), RYR1 (Affinity Capture-MS), TRDN (Reconstituted Complex), RYR1 (Proximity Label-MS), RYR1 (Reconstituted Complex), RYR1 (Reconstituted Complex), CALM1 (Reconstituted Complex), AKAP6 (Reconstituted Complex), RYR2 (Reconstituted Complex), RYR2 (Co-purification), RYR1 (Reconstituted Complex), RYR1 (Affinity Capture-MS)

ESM2 similar proteins: A2AGL3, B0LPN4, E9PZQ0, E9Q401, F1LMY4, F1Q8X5, P0C7A6, P11716, P11881, P16960, P21817, P29994, P29995, P30957, P42694, P48553, Q0VEJ0, Q14571, Q14643, Q15413, Q1LVW0, Q24498, Q28C34, Q3TLI0, Q5F361, Q5RCP7, Q6NRC7, Q6NRD0, Q6NYU2, Q6QI06, Q6R327, Q7SXV1, Q7Z3V4, Q7ZUV0, Q7ZYD9, Q80UK0, Q86VW0, Q8BHL5, Q8BIK4, Q8BWW9

Diamond homologs: A0A5F9C6I2, A1L252, A2VD92, B0LPN4, D3ZXK7, E9PZQ0, E9Q401, F1LMY4, O94712, P11716, P16960, P21817, P30957, P69566, Q15413, Q19614, Q1LUS8, Q28FM1, Q5R881, Q5XH91, Q5XPI3, Q5XPI4, Q6VN19, Q8BVR6, Q90WU3, Q92736, Q95LP3, Q96DX4, Q96S59, Q9PTY5, Q9VNV3, A2AGL3, P11881, P29993, P29994, P29995, P70227, Q14571, Q14573, Q14643

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
PRKG1	unknown	RYR1	phosphorylation
PRKACA	“up-regulates activity”	RYR1	phosphorylation
CAMK2G	unknown	RYR1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

10759 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	340
Likely pathogenic	334
Uncertain significance	4774
Likely benign	3979
Benign	310

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066439	NM_000540.3(RYR1):c.14582G>C (p.Arg4861Pro)	Pathogenic
1067471	NM_000540.3(RYR1):c.13994T>C (p.Leu4665Pro)	Pathogenic
1069457	NM_000540.3(RYR1):c.10619dup (p.Tyr3540Ter)	Pathogenic
1069514	NM_000540.3(RYR1):c.8773G>T (p.Glu2925Ter)	Pathogenic
1069774	NM_000540.3(RYR1):c.1381G>T (p.Glu461Ter)	Pathogenic
1071320	NM_000540.3(RYR1):c.13416del (p.Ile4473fs)	Pathogenic
1073108	NM_000540.3(RYR1):c.10471C>T (p.Gln3491Ter)	Pathogenic
1075282	NM_000540.3(RYR1):c.5917C>T (p.Gln1973Ter)	Pathogenic
1075694	NM_000540.3(RYR1):c.2005G>T (p.Glu669Ter)	Pathogenic
1076444	NM_000540.3(RYR1):c.12022C>T (p.Gln4008Ter)	Pathogenic
1180626	NM_000540.3(RYR1):c.9851G>A (p.Trp3284Ter)	Pathogenic
1217048	NM_000540.3(RYR1):c.6082C>T (p.Arg2028Ter)	Pathogenic
1253809	NM_000540.3(RYR1):c.8310+1G>T	Pathogenic
12969	NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg)	Pathogenic
12977	NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)	Pathogenic
12981	NM_000540.3(RYR1):c.12640_12648del (p.Arg4214_Phe4216del)	Pathogenic
12983	NM_000540.3(RYR1):c.10579C>T (p.Pro3527Ser)	Pathogenic
12986	NM_000540.3(RYR1):c.14587_14607del (p.Phe4863_Asp4869del)	Pathogenic
12987	NM_000540.2(RYR1):c.14647-1449A>G	Pathogenic
12990	NM_000540.3(RYR1):c.14365-2A>T	Pathogenic
12996	NM_000540.3(RYR1):c.13013_13032del (p.Ala4338fs)	Pathogenic
1323545	NM_000540.3(RYR1):c.10063C>T (p.Gln3355Ter)	Pathogenic
132992	NM_000540.3(RYR1):c.1021G>C (p.Gly341Arg)	Pathogenic
132994	NM_000540.3(RYR1):c.10348-6C>G	Pathogenic
133030	NM_000540.3(RYR1):c.1202G>A (p.Arg401His)	Pathogenic
1330358	NM_000540.3(RYR1):c.7879G>C (p.Val2627Leu)	Pathogenic
133040	NM_000540.3(RYR1):c.12700G>C (p.Val4234Leu)	Pathogenic
133061	NM_000540.3(RYR1):c.14210G>A (p.Arg4737Gln)	Pathogenic
133081	NM_000540.3(RYR1):c.14627A>G (p.Lys4876Arg)	Pathogenic
133116	NM_000540.3(RYR1):c.2455C>T (p.Arg819Ter)	Pathogenic

SpliceAI

13685 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38433870:GGACG:G	donor_gain	1.0000
19:38433871:GACG:G	donor_gain	1.0000
19:38433871:GACGG:G	donor_gain	1.0000
19:38433873:CGGT:C	donor_loss	1.0000
19:38433875:G:GG	donor_gain	1.0000
19:38440862:CAGG:C	donor_loss	1.0000
19:38440864:GGT:G	donor_loss	1.0000
19:38442343:C:G	acceptor_gain	1.0000
19:38442344:CCCA:C	acceptor_loss	1.0000
19:38442346:CA:C	acceptor_loss	1.0000
19:38442347:A:AG	acceptor_gain	1.0000
19:38442347:AGAAT:A	acceptor_gain	1.0000
19:38442348:G:GG	acceptor_gain	1.0000
19:38442348:GA:G	acceptor_gain	1.0000
19:38442348:GAA:G	acceptor_gain	1.0000
19:38442348:GAAT:G	acceptor_gain	1.0000
19:38442348:GAATG:G	acceptor_gain	1.0000
19:38442453:GGTG:G	donor_loss	1.0000
19:38442454:G:GA	donor_loss	1.0000
19:38442454:G:GG	donor_gain	1.0000
19:38443553:T:A	acceptor_gain	1.0000
19:38443554:GCA:G	acceptor_loss	1.0000
19:38443555:CAGTC:C	acceptor_loss	1.0000
19:38443556:A:AG	acceptor_gain	1.0000
19:38443557:G:GA	acceptor_gain	1.0000
19:38443557:GT:G	acceptor_gain	1.0000
19:38443557:GTC:G	acceptor_gain	1.0000
19:38443557:GTCA:G	acceptor_gain	1.0000
19:38443557:GTCAT:G	acceptor_gain	1.0000
19:38443628:GCATG:G	donor_gain	1.0000

AlphaMissense

33106 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:38444163:T:A	W147R	1.000
19:38444163:T:C	W147R	1.000
19:38455639:T:C	L560P	1.000
19:38455660:T:A	L567H	1.000
19:38455660:T:C	L567P	1.000
19:38463477:C:G	H878D	1.000
19:38463486:T:A	W881R	1.000
19:38463486:T:C	W881R	1.000
19:38463488:G:C	W881C	1.000
19:38463488:G:T	W881C	1.000
19:38463513:T:A	W890R	1.000
19:38463513:T:C	W890R	1.000
19:38463781:T:A	L906H	1.000
19:38466180:T:C	L987P	1.000
19:38466203:T:A	W995R	1.000
19:38466203:T:C	W995R	1.000
19:38466205:G:C	W995C	1.000
19:38466205:G:T	W995C	1.000
19:38444238:A:C	S172R	0.999
19:38444240:T:A	S172R	0.999
19:38444240:T:G	S172R	0.999
19:38444254:G:C	R177P	0.999
19:38444260:T:C	L179P	0.999
19:38444626:T:C	F194L	0.999
19:38444628:C:A	F194L	0.999
19:38444628:C:G	F194L	0.999
19:38444641:T:A	W199R	0.999
19:38444641:T:C	W199R	0.999
19:38446743:T:A	W259R	0.999
19:38446743:T:C	W259R	0.999

dbSNP variants (sampled 300 via entrez): RS1000029460 (19:38559825 T>G), RS1000041311 (19:38473070 G>T), RS1000077416 (19:38472862 T>G), RS1000096881 (19:38551780 C>G,T), RS1000162602 (19:38553524 C>G), RS1000163680 (19:38496139 A>C,G), RS1000169746 (19:38462190 C>T), RS1000171518 (19:38579563 C>T), RS1000194385 (19:38536391 A>G,T), RS1000214638 (19:38553180 C>G,T), RS1000217702 (19:38575537 G>A), RS1000296504 (19:38583965 C>T), RS1000313045 (19:38575709 A>G), RS1000339606 (19:38490523 C>T), RS1000345626 (19:38508886 T>C)

Disease associations

OMIM: gene MIM:180901 | disease phenotypes: MIM:145600, MIM:117000, MIM:255320, MIM:619542, MIM:160150, MIM:119800, MIM:615834, MIM:269400, MIM:617468, MIM:208150, MIM:160500, MIM:166710, MIM:601462, MIM:610542, MIM:108120, MIM:614408, MIM:614350

GenCC curated gene-disease

Disease	Classification	Inheritance
malignant hyperthermia, susceptibility to, 1	Definitive	Autosomal dominant
RYR1-related myopathy	Definitive	Autosomal dominant
congenital multicore myopathy with external ophthalmoplegia	Definitive	Autosomal recessive
central core myopathy	Strong	Autosomal dominant
autosomal recessive centronuclear myopathy	Supportive	Autosomal recessive
benign Samaritan congenital myopathy	Supportive	Autosomal recessive
lethal multiple pterygium syndrome	Supportive	Autosomal recessive
malignant hyperthermia of anesthesia	Supportive	Autosomal dominant
congenital myopathy with myasthenic-like onset	Supportive	Autosomal recessive
King-Denborough syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
malignant hyperthermia, susceptibility to, 1	Definitive	AD
RYR1-related myopathy	Definitive	AR
RYR1-related myopathy	Definitive	AD

Mondo (42): malignant hyperthermia, susceptibility to, 1 (MONDO:0007783), RYR1-related myopathy (MONDO:0100150), central core myopathy (MONDO:0007294), congenital fiber-type disproportion myopathy (MONDO:0009711), congenital multicore myopathy with external ophthalmoplegia (MONDO:0009712), King-Denborough syndrome (MONDO:0020485), malignant hyperthermia of anesthesia (MONDO:0018493), multiminicore myopathy (MONDO:0018948), congenital myopathy (MONDO:0019952), centronuclear myopathy (MONDO:0018947), ptosis (MONDO:0000728), malignant hyperthermia, susceptibility to (MONDO:0800188), clubfoot (MONDO:0007342), neuromuscular disease (MONDO:0019056), scoliosis (MONDO:0005392)

Orphanet (27): Malignant hyperthermia of anesthesia (Orphanet:423), Neurological muscular channelopathy due to a genetic ryanodine receptor defect (Orphanet:98742), Congenital fiber-type disproportion myopathy (Orphanet:2020), Central core disease (Orphanet:597), Multiminicore myopathy (Orphanet:598), Congenital multicore myopathy with external ophthalmoplegia (Orphanet:98905), Congenital myopathy (Orphanet:97245), Centronuclear myopathy (Orphanet:595), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Neuromuscular disease (Orphanet:68381), Congenital myopathy with cores (Orphanet:172976), Autism spectrum disorder due to AUTS2 deficiency (Orphanet:352490), Congenital cataract microcornea with corneal opacity (Orphanet:289499), Hydrops fetalis (Orphanet:1041), Arthrogryposis multiplex congenita (Orphanet:1037)

HPO phenotypes

223 total (30 of 223 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000054	Micropenis
HP:0000160	Narrow mouth
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000268	Dolichocephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000341	Narrow forehead
HP:0000369	Low-set ears
HP:0000411	Protruding ear
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000707	Abnormality of the nervous system
HP:0000750	Delayed speech and language development
HP:0000883	Thin ribs

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002875_93	Diisocyanate-induced asthma	5.000000e-06
GCST004618_49	White blood cell count (basophil)	4.000000e-22
GCST004631_6	Basophil percentage of white cells	2.000000e-18
GCST004634_53	Basophil percentage of granulocytes	3.000000e-16
GCST005727_3	Peanut allergy (parent-of-origin effect)	2.000000e-06
GCST009303_17	Abstraction and mental flexibility	6.000000e-06
GCST90000025_566	Appendicular lean mass	4.000000e-09
GCST90000027_45	Appendicular lean mass	6.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0007995	basophil percentage of granulocytes
EFO:0005939	parental genotype effect measurement
EFO:0007017	peanut allergy measurement
EFO:0009332	executive function measurement
EFO:0004980	appendicular lean mass

MeSH disease descriptors (19)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D001763	Blepharoptosis	C11.338.204
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D004827	Epilepsy	C10.228.140.490
D015160	Hydrops Fetalis	C12.050.703.277.060.480; C15.378.295.480; C15.378.420.826.100.350; C16.300.060.480; C16.320.365.826.100.350; C20.306.480; C23.888.277.395
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008305	Malignant Hyperthermia	C23.550.505.700; C23.550.767.600; C23.888.119.455.500
D009135	Muscular Diseases	C05.651; C10.668.491
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590
D020512	Myopathy, Central Core	C05.651.575.300; C10.668.491.550.300
D009468	Neuromuscular Diseases	C10.668
D010024	Osteoporosis	C05.116.198.579; C18.452.104.579
D012600	Scoliosis	C05.116.900.800.875
C563456	Colorectal Cancer, Hereditary Nonpolyposis, Type 5 (supp.)
C536883	King Denborough syndrome (supp.)
C537504	Kousseff Nichols syndrome (supp.)
C535694	Malignant hyperthermia susceptibility type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1846 (SINGLE PROTEIN), CHEMBL4106135 (PROTEIN COMPLEX)

PharmGKB: 1 entry (VIP=true, CPIC=true)

PharmGKB clinical annotations

48 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs111888148	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs112563513	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192116	Toxicity	3	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192122	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192124	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192161	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192162	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192163	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192167	Toxicity	3	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192168	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192170	Toxicity	3	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192172	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192172	Toxicity	3	HMG-CoA reductase inhibitors	Muscular Diseases
rs118192175	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192176	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192177	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192178	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118192178	Toxicity	3	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs118204423	Toxicity	3	succinylcholine;volatile anesthetics	Malignant Hyperthermia
rs121918592	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs121918593	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs121918594	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs121918595	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs121918596	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs144336148	Toxicity	3	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs1801086	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs186983396	Other	3	caffeine;chlorocresol	Malignant Hyperthermia
rs193922747	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922748	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922753	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922762	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922764	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922768	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922770	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922772	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922802	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922803	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922807	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922809	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia
rs193922816	Toxicity	1A	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Malignant Hyperthermia

PharmGKB variants

74 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1801086	RYR1	1A	101.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs28933396	RYR1	1A	102.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs28933397	RYR1	1A	102.75	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs63749869	RYR1	3	0.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs111888148	RYR1	1A	100.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs112563513	RYR1	1A	102.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192116	RYR1	3	0.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192122	RYR1	1A	103.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192123	RYR1		0.00	0
rs118192124	RYR1	1A	100.50	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192161	RYR1	1A	107.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192162	RYR1	1A	102.50	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192163	RYR1	1A	101.50	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192167	RYR1	3	0.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192170	RYR1	3	0.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192172	RYR1	1A	106.75	2	HMG-CoA reductase inhibitors;desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192175	RYR1	1A	100.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192176	RYR1	1A	103.75	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192177	RYR1	1A	103.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118192178	RYR1	1A	101.50	2	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs118204423	RYR1	3	0.25	1	succinylcholine;volatile anesthetics
rs121918592	RYR1	1A	104.75	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs121918593	RYR1	1A	105.50	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs121918594	RYR1	1A	101.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs121918595	RYR1	1A	100.75	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs142474192	RYR1		0.00	0
rs146429605	RYR1		0.00	0
rs147136339	RYR1		0.00	0
rs147213895	RYR1		0.00	0
rs148399313	RYR1		0.00	0
rs193922747	RYR1	1A	100.75	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922753	RYR1	1A	100.75	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922767	RYR1		0.00	0
rs193922770	RYR1	1A	101.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922772	RYR1	1A	102.50	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922802	RYR1	1A	101.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922803	RYR1	1A	100.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922807	RYR1	1A	100.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922809	RYR1	1A	100.25	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine
rs193922816	RYR1	1A	103.00	1	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine

PharmGKB dosing guidelines

1 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPIC	desflurane;enflurane;halothane;isoflurane;methoxyflurane;sevoflurane;succinylcholine	Annotation of CPIC Guideline for desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, succinylcholine and CACNA1S, RYR1		yes

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Ryanodine receptors (RyR)

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Ryanodine Derivative	IC50	3.3 nM

ChEMBL bioactivities

10 potent at pChembl≥5 of 19 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.74	Ki	1.8	nM	CHEMBL308183
8.48	IC50	3.3	nM	CHEMBL308183
8.46	IC50	3.5	nM	CHEMBL308183
5.66	EC50	2200	nM	BASTADIN 5
5.58	EC50	2600	nM	CHEMBL505907
5.24	EC50	5800	nM	CHEMBL504851
5.22	IC50	6000	nM	CHEMBL213853
5.20	EC50	6300	nM	BASTADIN 7
5.19	EC50	6500	nM	CHEMBL377812

PubChem BioAssay actives

10 with measured affinity, of 91 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2,6,9,11,13,14-hexahydroxy-3,7,10-trimethyl-11-propan-2-yl-15-oxapentacyclo[7.5.1.01,6.07,13.010,14]pentadecan-12-yl) 1H-pyrrole-2-carboxylate	198781: Binding to ryanodine receptor in canine cardiac membranes.	ki	0.0018	uM
(12Z,25Z)-5,16,21,32,36-pentabromo-4,20-dihydroxy-12,25-bis(hydroxyimino)-2,18-dioxa-10,27-diazapentacyclo[28.2.2.214,17.13,7.119,23]octatriaconta-1(32),3,5,7(38),14,16,19,21,23(35),30,33,36-dodecaene-11,26-dione	266719: Agonist like activity at skeletal junction sarcoplasmic reticulum RyR1/FKBP12 complex assessed as increase in [3H]ryanodine binding	ec50	2.2000	uM
(12Z,25Z)-5,16,21,32,33,36-hexabromo-4,20-dihydroxy-12,25-bis(hydroxyimino)-2,18-dioxa-10,27-diazapentacyclo[28.2.2.214,17.13,7.119,23]octatriaconta-1(32),3,5,7(38),14,16,19,21,23(35),30,33,36-dodecaene-11,26-dione	334201: Displacement of [3H]ryanodine from RyR1 calcium channel in sarcoplasmic reticulum assessed as calcium mobilization	ec50	2.6000	uM
(12Z,25E,29S)-5,16,21,32-tetrabromo-4,20,29-trihydroxy-12,25-bis(hydroxyimino)-2,18-dioxa-10,27-diazapentacyclo[28.2.2.214,17.13,7.119,23]octatriaconta-1(32),3,5,7(38),14,16,19,21,23(35),30,33,36-dodecaene-11,26-dione	334201: Displacement of [3H]ryanodine from RyR1 calcium channel in sarcoplasmic reticulum assessed as calcium mobilization	ec50	5.8000	uM
5,20-dibromo-4-hydroxy-2-oxa-10,14-diazatricyclo[16.2.2.13,7]tricosa-1(20),3,5,7(23),18,21-hexaene-11,15-dione	349210: Binding affinity to RYR1 channels by calcium mobilization assay	ic50	6.0000	uM
(12E,25E,28E)-5,16,21,32-tetrabromo-4,20-dihydroxy-12,25-bis(hydroxyimino)-2,18-dioxa-10,27-diazapentacyclo[28.2.2.214,17.13,7.119,23]octatriaconta-1(32),3,5,7(38),14,16,19,21,23(35),28,30,33,36-tridecaene-11,26-dione	349210: Binding affinity to RYR1 channels by calcium mobilization assay	ec50	6.3000	uM
2-azido-5-iodo-N-[4-[(13S)-5,19,21-tribromo-4-hydroxy-11,15-dioxo-2-oxa-10,14-diazatricyclo[16.2.2.13,7]tricosa-1(21),3,5,7(23),18(22),19-hexaen-13-yl]butyl]benzamide	266719: Agonist like activity at skeletal junction sarcoplasmic reticulum RyR1/FKBP12 complex assessed as increase in [3H]ryanodine binding	ec50	6.5000	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
chlorocresol	increases activity, increases expression, affects localization, increases transport, affects reaction (+4 more)	8
Calcium	increases activity, affects folding, affects activity, affects reaction, decreases reaction (+8 more)	7
Caffeine	increases activity, affects localization, increases response to substance, affects reaction, increases secretion	6
sodium arsenite	decreases expression, increases expression, increases reaction	4
Halothane	increases activity, affects localization, increases response to substance	3
Benzo(a)pyrene	affects methylation	2
Triclosan	affects binding, increases reaction, decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
2,3,6,2’,3’,6’-hexachlorobiphenyl	affects cotreatment, affects response to substance	1
decabromobiphenyl ether	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
oxymatrine	increases expression, increases reaction	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	decreases methylation	1
incobotulinumtoxinA	decreases expression	1
trametinib	decreases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, decreases expression	1
excavatolide B	increases expression	1
Decitabine	decreases expression, decreases reaction	1
Vorinostat	decreases expression	1
Antimony Potassium Tartrate	decreases expression	1
Arsenic	decreases expression, increases abundance	1

ChEMBL screening assays

16 unique, capped per target: 13 binding, 3 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006192	Binding	Binding affinity to RYR1 channels by calcium mobilization assay	Open-chain half-bastadins mimic the effects of cyclic bastadins on calcium homeostasis in cultured neurons. — Bioorg Med Chem Lett
CHEMBL802320	Functional	Potency compared to [3H]ryanodine for activity in canine ventricle.	Ryanodine action at calcium release channels. 1. importance of hydroxyl substituents. — J Med Chem

Cellosaurus cell lines

36 cell lines: 20 transformed cell line, 9 induced pluripotent stem cell, 5 cancer cell line, 2 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A2VI	GM26117	Transformed cell line	Female
CVCL_A2VL	GM26130	Transformed cell line	Male
CVCL_A2VP	GM26135	Transformed cell line	Female
CVCL_A2VQ	GM26136	Transformed cell line	Female
CVCL_A2VR	GM26137	Transformed cell line	Female
CVCL_A2VS	GM26147	Transformed cell line	Female
CVCL_A2VT	GM26153	Transformed cell line	Female
CVCL_A2VV	GM26155	Transformed cell line	Female
CVCL_A2WF	GM26186	Transformed cell line	Female
CVCL_A2WG	GM26199	Transformed cell line	Female

Clinical trials (associated diseases)

297 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00793988	PHASE4	COMPLETED	Vibration-Assisted Anaesthesia
NCT01239498	PHASE4	UNKNOWN	Saline Injection - Assisted Anesthesia in Eyelid Surgery
NCT02761083	PHASE4	WITHDRAWN	PMCF-study Using Novosyn® Quick Suture Material in Ophthalmic Surgery
NCT04007276	PHASE4	NOT_YET_RECRUITING	The Effect of Lumify™ on Ocular Redness, Intraocular Pressure, and Eyelid Position in Glaucoma Patients
NCT07390578	PHASE4	NOT_YET_RECRUITING	Upneeq vs. Lumify Ptosis
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT04766684	PHASE4	COMPLETED	Clubfoot Tenotomy Trial
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT02436759	PHASE3	COMPLETED	Study of the Safety and Efficacy of RVL-1201 in the Treatment of Acquired Blepharoptosis
NCT03536949	PHASE3	COMPLETED	Study of Safety of RVL-1201 in Treatment of Blepharoptosis
NCT03565887	PHASE3	COMPLETED	Study of Safety and Efficacy of RVL-1201 in the Treatment of Blepharoptosis
NCT05945615	PHASE3	COMPLETED	Oxymetazoline Drops for Acquired Blepharoptosis From Synkinesis
NCT06683651	PHASE3	RECRUITING	A Study in Chinese Patients With Acquired Blepharoptosis
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT03266081	PHASE2	WITHDRAWN	Bupivacaine Epiphora Trial
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation