Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.
Genetic Health Queensland, Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia.
Genet Med. 2021 Jun;23(6):1108-1115. doi: 10.1038/s41436-021-01107-y. Epub 2021 Feb 10.
ClinGen provides gene-specific guidance for interpretation of sequence variants in MYH7. We assessed laboratory and clinical impact of reclassification by the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) and ClinGen recommendations in 43 MYH7 variants reported by a diagnostic laboratory between 2013 and 2017.
Fifty-two proband reports containing MYH7 variants were reinterpreted by original ACMG-AMP and ClinGen guidelines. Evidence items were compared across schemes and reasons for classification differences recorded. Laboratory impact was assessed by number of recommended report reissues, and reclassifications coded as clinically "actionable" or "equivalent." Available pedigrees were reviewed to describe projected cascade impact.
ClinGen produced a higher proportion of diagnostic classifications (65% of variants) compared with ACMG-AMP (54%) and fewer variants of uncertain significance (30% versus 42%). ClinGen classification resulted in actionable changes in 18% of variants with equal upgrades and downgrades from original report. ClinGen's revisions to PM1 and PS4 contributed to classification differences in 21% and 19% of variants respectively. Each classification change per proband report impacted, on average, 3.1 cascade reports with a further 6.3 first- and second-degree relatives potentially available for genotyping per family.
ClinGen's gene-specific criteria provide expert-informed guidance for interpretation of MYH7 sequence variants. Periodic re-evaluation improves diagnostic confidence and should be considered by clinical and laboratory teams.
ClinGen 为解读 MYH7 中的序列变异提供了基因特异性指导。我们评估了在 2013 年至 2017 年间，一家诊断实验室报告的 43 个 MYH7 变异中，美国医学遗传学与基因组学学会-分子病理学协会（ACMG-AMP）和 ClinGen 推荐重新分类的实验室和临床影响。
对包含 MYH7 变异的 52 个先证者报告进行了重新解读，使用原始的 ACMG-AMP 和 ClinGen 指南进行解读。比较了不同方案中的证据项目，并记录了分类差异的原因。通过推荐的报告重新发布数量评估实验室影响，并对编码为临床“可操作”或“等效”的重新分类进行分类。对可用的家系进行了审查，以描述预期的级联影响。
与 ACMG-AMP（54%）相比，ClinGen 产生了更高比例的诊断分类（65%的变异），且不确定意义的变异更少（30%比 42%）。ClinGen 分类导致 18%的变异发生了可操作的变化，原始报告的升级和降级相等。ClinGen 对 PM1 和 PS4 的修订分别导致 21%和 19%的变异分类差异。每个先证者报告的分类变化平均影响 3.1 个级联报告，每个家庭还有 6.3 个第一和第二级亲属可供基因分型。
ClinGen 的基因特异性标准为解读 MYH7 序列变异提供了专家指导。定期重新评估可提高诊断信心，临床和实验室团队应考虑进行。
