Phenotypic Evidence for the Reclassification of the RYR1 p.(Glu4410Asp) Variant: From Uncertain Significance to Likely Benign.
5 affiliations
- 1Department of Anesthesiology, School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
- 2Defense and Veterans Consortium for Integrative Pain Management, Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA.
- 3Brenner Children's Hospital, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
- 4Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
- 5Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
Abstract
Malignant Hyperthermia Susceptibility (MHS) is most commonly caused by pathogenic variants in the RYR1 gene. The proliferation of RYR1 Variants of Uncertain Significance (VUS) on diagnostic genetic panels poses a significant clinical challenge, often leading to unnecessarily complex clinical concerns. We report the case of a 27-year-old African American female with a personal history of recurrent exertional rhabdomyolysis found to have a heterozygous RYR1 c.13230G>C p.(Glu4410Asp) variant. She later tested negative via the gold-standard Caffein-Halothane Contracture Test (CHCT). A negative CHCT test with an in silico Rare Exome Variant Ensemble Learner (REVEL) score of 0.171 meets the ClinGen MHS Variant Curation Expert Panel (VCEP) criteria for reclassification of the variant to Likely Benign. Additionally, the high allele frequency isolated within the African American (AA) population suggests a benign, ancestry-specific polymorphism maintained within the AA population rather than a pathogenic MHS mutation. Therefore, reclassifying the variant to Likely Benign prevents unnecessary muscle biopsies and alterations to perioperative anesthetic management and reduces the need for family cascade testing, and reduces use of potentially suboptimal alternative anesthetic protocols.
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BibTeX
@article{mullally2026phenotypic,
title = {{Phenotypic Evidence for the Reclassification of the RYR1 p.(Glu4410Asp) Variant: From Uncertain Significance to Likely Benign.}},
author = {Isabella Mullally and Eugene Smith and Peter Bedocs and Thomas Pranikoff and Leslie G Biesecker and Glen A Cook and Robert Vietor and Alakesh Bera},
journal = {Genes},
year = {2026},
month = oct,
doi = {10.3390/genes17101290},
url = {https://europepmc.org/article/MED/42938406},
note = {CC BY},
}
RIS
TY - JOUR
TI - Phenotypic Evidence for the Reclassification of the RYR1 p.(Glu4410Asp) Variant: From Uncertain Significance to Likely Benign.
AU - Isabella Mullally
AU - Eugene Smith
AU - Peter Bedocs
AU - Thomas Pranikoff
AU - Leslie G Biesecker
AU - Glen A Cook
AU - Robert Vietor
AU - Alakesh Bera
PY - 2026
DA - 2026/10/15
JO - Genes
DO - 10.3390/genes17101290
UR - https://europepmc.org/article/MED/42938406
AB - Malignant Hyperthermia Susceptibility (MHS) is most commonly caused by pathogenic variants in the RYR1 gene. The proliferation of RYR1 Variants of Uncertain Significance (VUS) on diagnostic genetic panels poses a significant clinical challenge, often leading to unnecessarily complex clinical concerns. We report the case of a 27-year-old African American female with a personal history of recurrent exertional rhabdomyolysis found to have a heterozygous RYR1 c.13230G>C p.(Glu4410Asp) variant. She later tested negative via the gold-standard Caffein-Halothane Contracture Test (CHCT). A negative CHCT test with an in silico Rare Exome Variant Ensemble Learner (REVEL) score of 0.171 meets the ClinGen MHS Variant Curation Expert Panel (VCEP) criteria for reclassification of the variant to Likely Benign. Additionally, the high allele frequency isolated within the African American (AA) population suggests a benign, ancestry-specific polymorphism maintained within the AA population rather than a pathogenic MHS mutation. Therefore, reclassifying the variant to Likely Benign prevents unnecessary muscle biopsies and alterations to perioperative anesthetic management and reduces the need for family cascade testing, and reduces use of potentially suboptimal alternative anesthetic protocols.
SN - 2073-4425
ER -