Systematic reclassification of RYR1 variants associated with Malignant Hyperthermia according to ACMG/AMP guidelines

Sultana, Shireen (2023) Systematic reclassification of RYR1 variants associated with Malignant Hyperthermia according to ACMG/AMP guidelines. Masters thesis, Indian Institute of Science Education, and Research Kolkata.

Text (MS dissertation of Shireen Sultana (18MS025)) Thesis_18MS025.pdf - Submitted Version Restricted to Repository staff only Download (535kB)

Abstract

Genetic testing plays an essential role in the diagnosis and management of Malignant Hyperthermia, a fatal pharmacogenetic disorder of skeletal muscle triggered by volatile anesthetics or succinylcholine. Three genes, RYR1, CACNA1S, and STAC3, are associated with MH susceptibility; however, most variants for Malignant Hyperthermia are in the RYR1 gene. The American College of Medical Genetics and Genomics and the Association for Molecular Pathology framework constitutes a classification system for Mendelian variants based on evidence criteria that assess variant frequency in the general population, variant types with disease causality, protein domains, and mutational hotspots implicated in disease, disease/ trait phenotypes in probands and families with observed segregation, in silico predictions and functional evidence. Evidence criteria are divided into those that support a benign and a pathogenic classification, with intermediate categories being likely pathogenic, uncertain significance, and likely benign, each with a suggested measure of strength, namely supporting, moderate, strong, or very strong. Curating the RYR1 pathogenic variants according to ACMG guidelines makes the variants more clinically relevant, as ACMG is a way to standardize the interpretation of the pathogenicity of variants.

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