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

Area of Science:

• Genetics
• Molecular Biology
• Bioinformatics

Background:

• Malignant hyperthermia (MH) is a severe pharmacogenetic disorder.
• RYR1 gene variants are a primary cause of autosomal dominant inherited MH.
• Standardized variant classification is crucial for accurate genetic testing and patient management.

Purpose of the Study:

• To adapt and refine the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for RYR1 variants associated with MH.
• To develop a quantitative framework for variant classification using Bayesian methods and likelihood ratios.
• To improve the accuracy and consistency of RYR1 variant interpretation in the context of MH.

Main Methods:

• Specified and piloted ACMG/AMP criteria for RYR1 and MH variant classification on 84 variants.
• Applied quantitative evidence calibration using likelihood ratios and the Bayesian framework.
• Evaluated in silico (PP3, BP4) and hotspot (PM1) criteria using REVEL scores and odds ratios.

Main Results:

• Seven ACMG/AMP criteria were adopted unchanged, nine were modified, and ten were dropped.
• Quantitative evaluation showed significant odds ratios for PP3 (23:1) and PM1 (24:1) criteria.
• Application of revised criteria to 44 known MH variants resulted in 29 pathogenic, 13 likely pathogenic, and 2 variants of uncertain significance classifications.

Conclusions:

• The adapted ACMG/AMP criteria provide a robust framework for classifying RYR1 variants related to MH.
• Quantitative calibration enhances the reliability of variant pathogenicity assessment.
• This approach facilitates accurate interpretation of RYR1/MH genomic testing results and is generalizable to other expert panels.