RYR1

Chr 19ADAR

ryanodine receptor 1

Also known as: CCO, CMYO1A, CMYO1B, CMYP1A, CMYP1B, KDS, MHS, MHS1

NCBI Gene: 6261 ENSG00000196218 UniProt: P21817 OMIM: 180901

This protein functions as a calcium release channel in the sarcoplasmic reticulum of skeletal muscle and connects the sarcoplasmic reticulum to transverse tubules. Mutations cause malignant hyperthermia susceptibility, central core disease, minicore myopathy with external ophthalmoplegia, and King-Denborough syndrome through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves gain-of-function effects on calcium channel activity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOF/LOFmechanismAD/ARLOEUF 0.464 OMIM phenotypes

VCEP Guidelines: Congenital MyopathiesReleased

ClinGen Panel

Clinical Summary— RYR1

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Gene-Disease Validity (ClinGen)

malignant hyperthermia, susceptibility to, 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.46LOEUF

pLI 0.000

Z-score 9.05

OE 0.38 (0.33–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.92Z-score

OE missense 0.90 (0.87–0.93)

2698 obs / 2993.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.33–0.46)

0≤0.351.4

Missense OE?0.90 (0.87–0.93)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 97 / 252.0Missense obs/exp: 2698 / 2993.3Syn Z: -2.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRYR1-related minicore myopathy with external ophthalmoplegiaLOFAR

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

Ryanodine receptor 1. GOF variants (enhanced calcium release) cause malignant hyperthermia susceptibility and central core disease (AD). LOF variants (reduced calcium release) cause recessive myopathies including multi-minicore disease. Mechanism is variant-specific.12

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6552th %ile

GOF

0.6833th %ile

LOF

0.3648th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNThese results suggest that the novel nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect.3

GOFAbout 50% of susceptible individuals carry dominant, gain-of-function mutations in RYR1 [which encodes ryanodine receptor type 1 (RyR1)], though they have normal muscle function and no overt clinical symptoms.4

LOFHaplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases.5

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References