变异标准的标准化对于准确解释遗传结果和患者的临床护理至关重要。由美国医学遗传学和基因组学学院(ACMG)和分子病理学协会(AMP)于2015年开发的变异管理指南被广泛使用,但不是基因特异性的。为了解决这个问题,临床基因组资源(ClinGen)变异型治疗专家组(VCEP)的任务是制定基因特异性变异型治疗指南.青光眼VCEP的创建是为了开发与原发性青光眼相关的基因的规则规范,包括肌蛋白(MYOC),最常见的原因是孟德尔青光眼。在28个ACMG/AMP标准中,青光眼VCEP对MYOC调整了15条规则,并确定13条规则不适用.关键规格包括确定次要等位基因频率阈值,制定计算先证者和隔离者的方法,并回顾功能测定。这些规则在81种变体上进行了试点,并导致在ClinVar中分类的40%的变体发生了分类变化,具有影响18个变体分类的功能证据。MYOC的标准化变体策展指南为实验室之间的规则一致应用提供了框架,改善青光眼管理中的MYOC基因检测。
The standardization of variant curation criteria is essential for accurate interpretation of genetic results and clinical care of patients. The variant curation
guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in 2015 are widely used but are not gene specific. To address this issue, the Clinical Genome Resource (ClinGen) Variant Curation Expert Panels (VCEP) have been tasked with developing gene-specific variant curation
guidelines. The Glaucoma VCEP was created to develop rule specifications for genes associated with primary glaucoma, including myocilin (MYOC), the most common cause of Mendelian glaucoma. Of the 28 ACMG/AMP criteria, the Glaucoma VCEP adapted 15 rules to MYOC and determined 13 rules not applicable. Key specifications included determining minor allele frequency thresholds, developing an approach to counting probands and segregations, and reviewing functional assays. The rules were piloted on 81 variants and led to a change in classification in 40% of those that were classified in ClinVar, with functional evidence influencing the classification of 18 variants. The standardized variant curation
guidelines for MYOC provide a framework for the consistent application of the rules between laboratories, to improve MYOC genetic testing in the management of glaucoma.