Background:Following an unexplained cardiac arrest, clinical genetic testing is increasingly becoming standard of care. Periodic review of variant classification is required, as reinterpretation can change the diagnosis, prognosis, and management of patients and their relatives.Methods:This study aimed to develop and validate a standardized algorithm to facilitate clinical application of the 2015 American College of Medical Genetics and Association for Molecular Pathology guidelines for the interpretation of genetic variants. The algorithm was applied to genetic results in the Cardiac Arrest Survivors With Preserved Ejection Fraction Registry, to assess the rate of variant reclassification over time. Variant classifications were then compared with the classifications of 2 commercial laboratories to determine the rate and identify sources of variant interpretation discordance.Results:Thirty-one percent of participants (40 of 131) had at least 1 genetic variant with a clinically significant reclassification over time. Variants of uncertain significance were more likely to be downgraded (73%) to benign than upgraded to pathogenic (27%; P=0.03). For the second part of the study, 50% (70 of 139) of variants had discrepant interpretations (excluding benign variants), provided by at least 1 team.Conclusions:Periodic review of genetic variant classification is a key component of follow-up care given rapidly changing information in the field. There is potential for clinical care gaps with discrepant variant interpretations, based on the interpretation and application of current guidelines. The development of gene- and disease-specific guidelines and algorithms may provide an opportunity to further standardize variant interpretation reporting in the future.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT00292032.

中文翻译：

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临床医生和临床商业实验室对保留射血分数的心脏骤停幸存者的变异重新解释（保留射血分数的心脏骤停幸存者）

背景：在不明原因的心脏骤停后，临床基因检测正日益成为护理标准。需要对变异分类进行定期审查，因为重新解释会改变患者及其亲属的诊断、预后和管理。方法：本研究旨在开发和验证标准化算法，以促进 2015 年美国医学遗传学会的临床应用和用于解释遗传变异的分子病理学协会指南。该算法应用于保留射血分数登记的心脏骤停幸存者的遗传结果，以评估随时间变化的变异重新分类率。然后将变异分类与 2 个商业实验室的分类进行比较，以确定变异解释不一致的发生率和来源。结果：31% 的参与者（131 名中的 40 名）至少有 1 个遗传变异，随着时间的推移具有临床意义的重新分类. 意义不确定的变异更有可能被降级（73%）为良性，而不是升级为致病（27%；P = 0.03)。对于研究的第二部分，至少 1 个团队提供了 50%（139 个中的 70 个）变异的解释不一致（不包括良性变异）。结论：遗传变异分类的定期审查是后续护理的关键组成部分鉴于该领域的快速变化的信息。根据当前指南的解释和应用，临床护理可能存在差异解释差异。基因和疾病特异性指南和算法的发展可能为将来进一步标准化变异解释报告提供机会。注册：URL：https://www.clinicaltrials.gov；唯一标识符：NCT00292032。