ArticleHuman molecular genetics2022
Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility.
Article in Human molecular genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it, 52 citations in OpenAlex.
- JSA guideline for management of malignant hyperthermia in 2025.Journal of anesthesia · 2026Guideline
- Estimating the Prevalence of Malignant Hyperthermia Susceptibility Based on CausativeInternational journal of molecular sciences · 2026Article
- Monogenic Syndromes as a Cause of Adverse Drug Reactions in the Russian Population.International journal of molecular sciences · 2026Article
- EMQN Best Practice Guidelines for Genetic Testing and Reporting in RYR1-related disorders.European journal of human genetics : EJHG · 2026Review
- A proposed North American approach for genetic testing of individuals at risk for malignant hyperthermia.Canadian journal of anaesthesia = Journal canadien d'anesthesie · 2026Review
- A Proposed North American Approach for Genetic Testing of Individuals at Risk for Malignant Hyperthermia.Anesthesiology · 2026Article
- Clinical and Genetic Spectrum ofMolecular syndromology · 2026Article
- Humidity impacts volatile anesthetic and heat responses of malignant hyperthermia susceptible mice.Skeletal muscle · 2026Article
- Recognition of a Critical Functional Domain and ImprovedHuman mutation · 2026Article
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- Succinylcholine-induced rhabdomyolysis in a patient withBiomolecules & biomedicine · 2025Article
- Genetic Testing for Malignant Hyperthermia Susceptibility-Threading the Needle in the Haystack.Genes · 2025Review
- Article
- Calibrating a functional assay for variant classification in RYR1-related malignant hyperthermia susceptibility.Human molecular genetics · 2025Article
- Updating probability of pathogenicity for RYR1 and CACNA1S exon variants in individuals without malignant hyperthermia after exposure to triggering anesthetics.Pharmacogenetics and genomics · 2025Article
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- Complementary Roles of Structure and Variant Effect Predictors in RyR1 Clinical Interpretation.Human mutation · 2025Article
- The history and future of pharmacogenetics in Aotearoa/New Zealand.Journal of the Royal Society of New Zealand · 2025Review
- Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource's FBN1 variant curation expert panel.Genome medicine · 2024Article
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Authors and funding
18 authors at 10 institutions in 5 countries.
Funding
Abstract
The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.