PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

中文翻译：

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MYH7 相关遗传性心肌病 ACMG/AMP 变异分类框架的调整和验证：ClinGen 遗传性心肌病专家小组的建议。

目的在临床护理中整合基因组测序需要标准化变异解释实践。临床基因组资源已经建立了专家小组，以适应美国医学遗传学和基因组学学会/分子病理学协会针对特定基因和疾病的分类框架。心肌病专家小组选择 MYH7（遗传性心肌病的主要贡献者）作为试验基因，以开发一种广泛适用的方法。方法专家修订版通过临床和诊断实验室专家对的结构化双重审查对 60 种变体进行了测试。最终共识规则是通过反复讨论建立的。结果调整代表疾病/基因知情规范 (12) 或现有规则的强度调整 (5)。九项规则被认为不适用。关键规范包括次要等位基因频率阈值的定量框架、分离数据的使用以及在缺乏完全受控的病例对照研究的情况下计算多个独立变异发生的半定量方法。最初的专家间分类一致性为 93%。来自参与诊断实验室的内部数据改变了 20% 变体 (n = 12) 的分类，突出了数据共享的关键重要性。结论这些调整后的规则结合专家审查和临床判断提高了用于 MYH7 相关疾病的特异性并作为具有相似遗传和临床特征的基因和疾病的垫脚石。以及一种半定量的方法来计算缺乏完全控制的病例对照研究的多个独立变异发生。最初的专家间分类一致性为 93%。来自参与诊断实验室的内部数据改变了 20% 变体 (n = 12) 的分类，突出了数据共享的关键重要性。结论这些调整后的规则结合专家审查和临床判断提高了用于 MYH7 相关疾病的特异性并作为具有相似遗传和临床特征的基因和疾病的垫脚石。以及一种半定量的方法来计算缺乏完全控制的病例对照研究的多个独立变异发生。最初的专家间分类一致性为 93%。来自参与诊断实验室的内部数据改变了 20% 变体 (n = 12) 的分类，突出了数据共享的关键重要性。结论这些调整后的规则结合专家审查和临床判断提高了用于 MYH7 相关疾病的特异性并作为具有相似遗传和临床特征的基因和疾病的垫脚石。