Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility.
Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility.
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DOI：
10.1038/s41436-021-01125-w
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Biesecker LG
中科院分区：
文献类型：
--
作者：
Johnston JJ;Dirksen RT;Girard T;Gonsalves SG;Hopkins PM;Riazi S;Saddic LA;Sambuughin N;Saxena R;Stowell K;Weber J;Rosenberg H;Biesecker LG
作为ClinGen专家组（EP），我们着手调整ACMG致病性标准，将RYR 1变异体分类为与常染色体显性遗传恶性高热（MH）相关。我们为RYR 1和MH的变异分类指定了ACMG/AMP标准。拟议的规则在84个变体上进行了试点。我们应用定量证据校准的几个标准，使用基于贝叶斯框架的似然比。7个ACMG/AMP标准被采用，没有变化，9个标准被采用RYR 1特定的修改，10个标准被删除。对计算机模拟（PP 3和BP 4）和热点标准（PM 1）进行了定量评价。使用≥0.85（致病性）和≤0.5（良性）的截断值，REVEL得出PP 3的比值比（OR）为23：1，BP 4的比值比（OR）为14：1。PM 1热点标准的OR为24：1。PP 3和PM 1以中等强度实施。将修订后的ACMG标准应用于44种公认的MH变体，其中29种被归类为致病性，13种被归类为可能致病性，2种被归类为意义不确定的变体。这些变异体的固化将有助于RYR 1/MH基因组检测结果的分类，这对于次要结果分析尤其重要。我们的定量校准标准的方法可推广到其他变异策展专家小组。
As a ClinGen Expert Panel (EP) we set out to adapt the ACMG 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 hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cut-offs 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 criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and two 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.
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DOI：
10.1038/gim.2017.218
发表时间：
2018-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
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发表时间：
2013-07
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
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DOI：
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