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

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

SUBMITTER: Johnston JJ 

PROVIDER: S-EPMC8263483 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature