Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Pharmacology and Physiology, University of Rochester Medical School, Rochester, NY, USA.
Genet Med. 2021 Jul;23(7):1288-1295. doi: 10.1038/s41436-021-01125-w. Epub 2021 Mar 25.
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).
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.
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 an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance.
Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.
作为 ClinGen 专家小组 (EP)，我们着手改编美国医学遗传学与基因组学学院 (ACMG)/分子病理学协会 (AMP) 的致病性标准，以将 RYR1 变异分类为常染色体显性遗传恶性高热 (MH)。
我们指定了 RYR1 和 MH 的 ACMG/AMP 变异分类标准。将提议的规则在 84 个变体上进行了试点。我们使用基于贝叶斯框架的似然比对几个标准进行了定量证据校准。
采用了七个 ACMG/AMP 标准，未作修改；九个标准采用了 RYR1 特异性修改；十个标准被删除。对体外（PP3 和 BP4）和热点（PM1）标准进行了定量评估。REVEL 使用≥0.85（致病性）和≤0.5（良性）的三分截断值，对 PP3 和 BP4 给出了 23:1 的优势比 (OR)。PM1 热点标准的 OR 为 24:1。PP3 和 PM1 的实施强度为中等。将修订后的 ACMG/AMP 标准应用于 44 种公认的 MH 变体，29 种被归类为致病性，13 种为可能致病性，2 种为意义不明的变异。
对这些变体进行分类将有助于 RYR1/MH 基因组检测结果的分类，这对于二级发现分析尤为重要。我们对标准进行定量校准的方法可推广到其他变体分类专家小组。
