. 2021 Jul;23(7):1288-1295.

doi: 10.1038/s41436-021-01125-w. Epub 2021 Mar 25.

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility

Affiliations

¹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. jjohnsto@mail.nih.gov.
² Department of Pharmacology and Physiology, University of Rochester Medical School, Rochester, NY, USA.
³ Department of Anesthesiology, University of Basel, Basel, Switzerland.
⁴ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ MH Unit, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
⁶ Department of Anesthesia and Pain Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
⁷ Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Consortium for Health and Military Performance, Uniformed Services University Health Science, Bethesda, MD, USA.
⁹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.
¹¹ Prevention Genetics, Marshfield, WI, USA.
¹² MH Association of the United States, Sherburne, NY, USA.
¹³ NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

PMID: 33767344
PMCID: PMC8263483
DOI: 10.1038/s41436-021-01125-w

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility

Jennifer J Johnston et al. Genet Med. 2021 Jul.

. 2021 Jul;23(7):1288-1295.

doi: 10.1038/s41436-021-01125-w. Epub 2021 Mar 25.

Authors

Affiliations

¹ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. jjohnsto@mail.nih.gov.
² Department of Pharmacology and Physiology, University of Rochester Medical School, Rochester, NY, USA.
³ Department of Anesthesiology, University of Basel, Basel, Switzerland.
⁴ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
⁵ MH Unit, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
⁶ Department of Anesthesia and Pain Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.
⁷ Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, USA.
⁸ Consortium for Health and Military Performance, Uniformed Services University Health Science, Bethesda, MD, USA.
⁹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰ School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.
¹¹ Prevention Genetics, Marshfield, WI, USA.
¹² MH Association of the United States, Sherburne, NY, USA.
¹³ NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

PMID: 33767344
PMCID: PMC8263483
DOI: 10.1038/s41436-021-01125-w

Abstract

Purpose: As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH).

Methods: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.

Results: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance.

Conclusion: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest:

LGB has received in kind research support from ArQule, Inc (now wholly owned by Merck, Inc) and honoraria from Cold Spring Harbor Press.

Figures

**Figure 1.**
Cumulative HEK293 transfection assay data for RYR1 variants from the literature. Variants are grouped according to pathogenicity assessment without consideration of PS3/BS3 (functional data).

**Figure 2.**
Decision tree for weighting functional evidence PS3/BS3.

See this image and copyright information in PMC

References

1. Gonsalves SG, Dirksen RT, Sangkuhl K et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin Pharmacol Ther (2018). - PMC - PubMed
1. Rosenberg H, Sambuughin N, Riazi S & Dirksen R Malignant Hyperthermia Susceptibility. in GeneReviews((R)) (eds. Adam MP et al.) (University of Washington, Seattle (WA), 1993).
1. Monnier N, Krivosic-Horber R, Payen JF et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 97, 1067–74 (2002). - PubMed
1. Carpenter D, Robinson RL, Quinnell RJ et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth 103, 538–48 (2009). - PubMed
1. Green RC, Berg JS, Grody WW et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15, 565–74 (2013). - PMC - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Molecular Biology Databases
- The Weizmann Institute of Science GeneCards and MalaCards databases
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility

Affiliations

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials