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Updated: Sep 4, 2025
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related
Jennifer J Johnston1, Robert T Dirksen2, Thierry Girard3
1Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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.
Insights
New guidelines for RYR1-related malignant hyperthermia susceptibility (MHS) were established, classifying 251 variants. RYR1-related MHS may be more prevalent than previously thought, requiring further functional studies.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacogenomics
Background:
- The ClinGen malignant hyperthermia susceptibility (MHS) expert panel previously established ACMG/AMP criteria for RYR1-related MHS.
- A pilot study analyzed 84 RYR1 variants, necessitating further comprehensive variant classification.
Purpose of the Study:
- To classify an additional 251 RYR1 variants associated with MHS using updated ClinGen standards.
- To refine the ACMG/AMP criteria for RYR1-related MHS variant interpretation.
- To estimate the prevalence of RYR1-related MHS.
Main Methods:
- Revised ACMG/AMP criteria for RYR1-related MHS, modifying criteria PS4, PS1, PM5, and PM1.
- Classified 251 RYR1 variants based on the updated criteria.
- Utilized posterior probabilities and gnomAD frequencies to estimate variant prevalence.
Main Results:
- Classified 42 variants as Pathogenic/Likely Pathogenic (P/LP), 16 as Benign/Likely Benign (B/LB), and 193 as Variants of Uncertain Significance (VUS).
- Insufficient evidence was the primary reason for VUS classifications (175 variants).
- Estimated RYR1-related MHS prevalence between 1/300 and 1/1075, higher than current estimates.
Conclusions:
- Updated ACMG/AMP criteria and classified 251 RYR1 variants for MHS.
- A significant number of VUS classifications highlight the need for prioritized functional studies.
- RYR1-related MHS pathogenic variants are likely more common than currently recognized.
