Background:Missense variants in the MYH7-encoded MYH7 (beta myosin heavy chain 7) represent a leading cause of hypertrophic cardiomyopathy (HCM). MYH7-specific American College of Medical Genetics and Genomics (ACMG) variant classification guidelines were released recently but have yet to be assessed independently. We set out to assess the performance of the MYH7-specific ACMG guidelines and determine if the addition of phenotype-enhanced criteria (PE-ACMG) using the HCM Genotype Predictor Score can further reduce the burden of variants of uncertain significance (VUS).Methods:Re-assessment was performed on 70 MYH7-variants in 121 unique patients from Mayo Clinic, and an independent cohort of 54 variants in 70 patients from Royal Prince Alfred Hospital (Australia). Qualifying variants were re-adjudicated using both standard ACMG and MYH7-ACMG guidelines, and HCM Genotype Predictor Score was used to provide a validated measure of strength of clinical phenotype to be incorporated into the MYH7-ACMG framework.Results:Among Mayo Clinic identified variants, 11/70 (16%) were classified as pathogenic (P), 10/70 (14%) as likely pathogenic, and 49/70 (70%) as a VUS. A similar distribution was seen in the Australian patients (12/54 [22%] P, 12/54 [22%] likely pathogenic, and 30/54 [56%] VUS; P=not significant). Application of the MYH7-ACMG resulted in a nonsignificant reduction of the VUS burden in both cohorts from 49/70 to 39/70 (56%; P=0.1; Mayo Clinic) and from 30/54 to 20/54 (37%; P=0.1; Australia). Using the combined PE-MYH7-ACMG framework, the VUS decreased significantly from 49 to 27 (P<0.001, Mayo Clinic) and from 30 to 16 (P<0.001; Australia).Conclusions:Use of the MYH7-specific guidelines alone failed to significantly decrease VUS burden in 2 independent cohorts. However, a significant reduction in VUS burden was observed after the addition of phenotypic criteria. Using a patient’s strength of sarcomeric HCM phenotype for variant adjudication can increase significantly the clinical utility of genetic testing for patients with HCM.

中文翻译：

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表型增强型 MYH7 特异性变体分类框架在肥厚性心肌病基因检测中的临床效用。

背景：MYH7编码的 MYH7（β 肌球蛋白重链 7）中的错义变异是肥厚型心肌病 (HCM) 的主要原因。最近发布了 MYH7特定的美国医学遗传学和基因组学学院 (ACMG) 变异分类指南，但尚未进行独立评估。我们着手评估特定于MYH7 的ACMG 指南的性能，并确定使用 HCM 基因型预测器评分添加表型增强标准 (PE-ACMG) 是否可以进一步减少不确定意义的变异 (VUS) 的负担。 :重新评估了 70 MYH7-来自 Mayo Clinic 的 121 名独特患者的变异，以及来自皇家阿尔弗雷德王子医院（澳大利亚）的 70 名患者的 54 种变异的独立队列。使用标准 ACMG 和MYH7 -ACMG 指南重新判定符合条件的变异，并使用 HCM 基因型预测评分来提供临床表型强度的有效衡量标准，以纳入MYH7 -ACMG 框架。 结果：在 Mayo Clinic 中发现的变异, 11/70 (16%) 被归类为致病性 (P)，10/70 (14%) 被归类为可能致病性，49/70 (70%) 被归类为 VUS。在澳大利亚患者中观察到类似的分布（12/54 [22%] P，12/54 [22%] 可能致病，30/54 [56%] VUS；P = 不显着）。MYH7的应用-ACMG 使两个队列的 VUS 负担从 49/70 减少到 39/70（56%；P =0.1；Mayo Clinic）和从 30/54 减少到 20/54（37%；P =0.1；澳大利亚）。使用组合的 PE-MYH7-ACMG 框架，VUS 从 49 显着降低到 27（P <0.001，Mayo Clinic）和从 30显着降低到 16（P <0.001；澳大利亚）。结论：使用MYH7- 单独的特定指南未能显着降低 2 个独立队列中的 VUS 负担。然而，在添加表型标准后，观察到 VUS 负担显着减少。使用患者的肌节 HCM 表型强度进行变异判定可以显着增加基因检测对 HCM 患者的临床效用。