RYR1-related myopathy

Summary

RYR1-related myopathy (MONDO:0100150) is a disease (an umbrella term covering 5 Mondo subtypes) caused by RYR1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: RYR1 (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 108

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	RYR1-related myopathy
Mondo ID	MONDO:0100150
Orphanet	98742
GARD	0026064
Is cancer (heuristic)	no

Also known as: neurological muscular channelopathy due to a genetic ryanodine receptor defect · RYR1-related disease · RYR1-related disorder · RYR1-related myopathy

Data availability: 108 ClinVar variants · 36 ClinGen variant curations · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › RYR1-related myopathy

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Subtypes (5): central core myopathy, congenital multicore myopathy with external ophthalmoplegia, congenital myopathy with myasthenic-like onset, King-Denborough syndrome, rhabdomyolysis-myalgia syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

108 retrieved; paginated sample, class counts are floors:

41 uncertain significance, 15 likely pathogenic, 13 conflicting classifications of pathogenicity, 12 pathogenic, 8 pathogenic/likely pathogenic, 7 likely benign, 6 benign, 1 uncertain significance; drug response, 1 conflicting classifications of pathogenicity; drug response, 1 drug response, 1 benign/likely benign, 1 pathogenic; drug response, 1 pathogenic/likely pathogenic; drug response

ClinVar	Variant (HGVS)	Gene	Classification	Review
1180698	NM_000540.3(RYR1):c.14437C>T (p.His4813Tyr)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1253809	NM_000540.3(RYR1):c.8310+1G>T	RYR1	Pathogenic	reviewed by expert panel
12996	NM_000540.3(RYR1):c.13013_13032del (p.Ala4338fs)	RYR1	Pathogenic	reviewed by expert panel
132994	NM_000540.3(RYR1):c.10348-6C>G	RYR1	Pathogenic	reviewed by expert panel
133030	NM_000540.3(RYR1):c.1202G>A (p.Arg401His)	RYR1	Pathogenic	reviewed by expert panel
133098	NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)	RYR1	Pathogenic/Likely pathogenic	reviewed by expert panel
133202	NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)	RYR1	Pathogenic; drug response	reviewed by expert panel
1341369	NM_000540.3(RYR1):c.7614+1G>A	RYR1	Pathogenic	criteria provided, single submitter
224998	NM_000540.3(RYR1):c.10347+1G>A	RYR1	Pathogenic	reviewed by expert panel
265505	NM_000540.3(RYR1):c.14416A>G (p.Asn4806Asp)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2920711	NM_000540.3(RYR1):c.10865del (p.Lys3622fs)	RYR1	Pathogenic	criteria provided, single submitter
3376786	NM_000540.3(RYR1):c.7706_7707del (p.Phe2569fs)	RYR1	Pathogenic	criteria provided, single submitter
42098	NM_000540.3(RYR1):c.10204T>G (p.Cys3402Gly)	RYR1	Pathogenic	reviewed by expert panel
451330	NM_000540.3(RYR1):c.9472+1G>A	RYR1	Pathogenic	reviewed by expert panel
4531722	NM_000540.3(RYR1):c.14761T>C (p.Phe4921Leu)	RYR1	Pathogenic	criteria provided, single submitter
590392	NM_000540.3(RYR1):c.11929C>T (p.Gln3977Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590394	NM_000540.3(RYR1):c.12063_12064dup (p.Met4022fs)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
642707	NM_000540.3(RYR1):c.8888T>C (p.Leu2963Pro)	RYR1	Pathogenic	reviewed by expert panel
653142	NM_000540.3(RYR1):c.13892A>C (p.Tyr4631Ser)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65979	NM_000540.3(RYR1):c.7354C>T (p.Arg2452Trp)	RYR1	Pathogenic/Likely pathogenic; drug response	reviewed by expert panel
852784	NM_000540.3(RYR1):c.9157C>T (p.Arg3053Ter)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
870400	NM_000540.3(RYR1):c.5989G>A (p.Glu1997Lys)	RYR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1214002	NM_000540.3(RYR1):c.7084G>A (p.Glu2362Lys)	RYR1	Likely pathogenic	reviewed by expert panel
1341368	NM_000540.3(RYR1):c.14650T>C (p.Tyr4884His)	RYR1	Likely pathogenic	criteria provided, single submitter
1341374	NM_000540.3(RYR1):c.2792T>C (p.Leu931Pro)	RYR1	Likely pathogenic	criteria provided, single submitter
1524261	NM_000540.3(RYR1):c.46-1G>A	RYR1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412687	NM_000540.3(RYR1):c.14488T>C (p.Ser4830Pro)	RYR1	Likely pathogenic	criteria provided, single submitter
2674604	NM_000540.3(RYR1):c.3178+587A>G	RYR1	Likely pathogenic	criteria provided, single submitter
2710027	NM_000540.3(RYR1):c.10171G>T (p.Glu3391Ter)	RYR1	Likely pathogenic	reviewed by expert panel
3233276	NM_000540.3(RYR1):c.345G>A (p.Met115Ile)	RYR1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RYR1	Definitive	Autosomal dominant	RYR1-related myopathy	22

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RYR1	Ryanodine receptor 1	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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RYR1	2,177

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RYR1	P21817	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ion homeostasis	1	203.9×	0.016	RYR1
Stimuli-sensing channels	1	135.9×	0.016	RYR1
Cardiac conduction	1	108.8×	0.016	RYR1
Ion channel transport	1	96.0×	0.016	RYR1
Muscle contraction	1	77.2×	0.016	RYR1
Transport of small molecules	1	25.1×	0.040	RYR1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to caffeine	1	2407.4×	0.003	RYR1
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	1685.2×	0.003	RYR1
cellular response to caffeine	1	1532.0×	0.003	RYR1
ossification involved in bone maturation	1	1404.3×	0.003	RYR1
striated muscle contraction	1	842.6×	0.004	RYR1
skeletal muscle fiber development	1	543.6×	0.005	RYR1
skin development	1	443.5×	0.005	RYR1
regulation of cytosolic calcium ion concentration	1	383.0×	0.005	RYR1
release of sequestered calcium ion into cytosol	1	343.9×	0.005	RYR1
outflow tract morphogenesis	1	306.4×	0.005	RYR1
protein homotetramerization	1	237.3×	0.006	RYR1
muscle contraction	1	208.1×	0.006	RYR1
cellular response to calcium ion	1	200.6×	0.006	RYR1
calcium ion transport	1	181.2×	0.006	RYR1
response to hypoxia	1	95.8×	0.010	RYR1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RYR1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RYR1	16	Binding:13, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.