Evidence map›Paper›PMID 40192509›Full record

ArticleHuman molecular genetics2025

Calibrating a functional assay for variant classification in RYR1-related malignant hyperthermia susceptibility.

Evan Z Ying, Amber Douglass, Marwan A Hawari, Linda Groom, Kathryn Stowell, Robert T Dirksen, Jennifer J Johnston, Leslie G Biesecker

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In one paragraph

Article in Human molecular genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

8 authors.

Evan Z YingCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892, United States.ORCID 0009-0004-4629-9826
Amber DouglassCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892, United States.
Marwan A HawariCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892, United States.
Linda GroomDepartment of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, United States.
Kathryn StowellSchool of Food Technology and Natural Sciences, Massey University, Tennent Drive, Palmerston North 4410, New Zealand.
Robert T DirksenDepartment of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, United States.
Jennifer J JohnstonCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892, United States.ORCID 0000-0002-1012-6358
Leslie G BieseckerCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, 50 South Drive, Bethesda, MD 20892, United States.ORCID 0000-0002-0197-3811

Funding

Environmental and Epigenetic Modifiers of Susceptibility to Malignant Hyperthermia and Environmental Heat StrokeR01AR082209 · NIAMS · BAYLOR COLLEGE OF MEDICINE · PI JAMES J DOWLING, Robert T Dirksen · 2023 to 2026
$2.9M
National Institutes of Health, National Human Genome Research Institute HG200328-19National Institutes of Health, National Human Genome Research Institute HG200359-16National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases AR082209-03NIAMS NIH HHS R01 AR082209
6 · The paper itself

Abstract

purposeIdentifying individuals with pathogenic variants for RYR1-related Malignant Hyperthermia Susceptibility (MHS) could reduce morbidity and mortality due to MH reactions. Realization of this goal requires knowledge of variant pathogenicity, and proper weighting of functional assays is important for accurate variant classification. Caffeine-induced Ca2+ release assays can be used to support pathogenicity per the ClinGen Variant Curation Expert Panel (VCEP). However, the caffeine-induced Ca2+ release assay lacks formal validation with known pathogenic and benign variants.

methodsFifteen benign/likely benign and six pathogenic/likely pathogenic RYR1 variants were used to calibrate the caffeine-induced Ca2+ release assay using a multi-mode microplate reader. Five variants of unknown significance (VUS) were assayed for possible reclassification.

resultsOur data support use of the caffeine-induced Ca2+ release assay at a moderate weight per the American College of Medical Genetics and Genomics pathogenicity criteria schema with a positive likelihood ratio of 12.14:1 (pathogenicity) and a negative likelihood ratio of 0.22:1 (4.5:1 benignity). Using this validated assay, two of five VUS were reclassified as likely benign.

conclusionFormal validation of the caffeine-induced Ca2+ release assay supports the VCEP functional criteria weighting at moderate strength based on these data. Additional variants should be assayed to shift more from VUS to benign or pathogenic classifications.

Indexed as

Genetic Predisposition to DiseaseMalignant HyperthermiaRyanodine Receptor Calcium Release ChannelCaffeineCalciumGenetic VariationHumansCaffeineCalciumRyanodine Receptor Calcium Release ChannelRYR1 protein, humanCalcium Release AssayMalignant Hyperthermia SusceptibilityRYR1Variant Classification

Identifiers

PMID40192509
PMCPMC13031167

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