Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1 -related malignant hyperthermia susceptibility

作者：Jennifer J. Johnston, Robert T. Dirksen, Thierry Girard, Philip M. Hopkins, Natalia Kraeva, Ognoon Mungunsukh, K. Bailey Radenbaugh, Sheila Riazi, Rachel L. Robinson, Louis Saddic, Nyamkhishig Sambuughin, Richa Saxena, Sarah Shepherd, Kathryn M. Stowell, James L. Weber, Seeley Yoo, Henry Rosenberg, Leslie G. Biesecker · 发表于：Human Molecular Genetics · 年份：2022 · DOI：10.1093/hmg/ddac145 · 被引用次数：59 · 研究领域：Ion channel regulation and function、Genomics and Rare Diseases、Erythrocyte Function and Pathophysiology

The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the American College of Medical Genetics and Genomics/Association of Molecular Pathologists (ACMG/AMP) criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Criteria PS1 and PM5 were revised to consider LP variants at the same amino-acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 175 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1075, considerably higher than current estimates. We have updated ACMG/AM...