Abstract：
In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.
The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.
The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.
Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.
The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.
The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.
Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.
摘要：
2015年，美国医学遗传学和基因组学学院（ACMG）和分子病理学协会（AMP）发布了孟德尔疾病序列水平变异分类的共识标准化指南。为了提高准确性和一致性，临床基因组资源家族性高胆固醇血症(FH)变异型固化专家小组的任务是优化现有的ACMG/AMP框架,用于FH的疾病特异性分类.在这项研究中,我们为最常见的FH相关基因提供了共识建议，LDLR,其中已鉴定出大于2300个独特的FH相关变体。
多学科的FH变体管理专家小组亲自会面，并通过频繁的电子邮件和电话会议制定ACMG/AMP指南的LDLR特定修改。通过迭代，试点测试,辩论,和评论，专家达成共识。
对现有ACMG/AMP指南的一致LDLR变体修改包括（1）改变人群频率阈值，(2)函数损失变体类型的划分，（3）功能研究标准规范，（4）共隔离标准规范，(5)仿真预测工具的具体用途和阈值，在其他人中。
建立这些指南作为临床实验室设置的新标准将导致更多的证据，全球LDLR变体分类的统一方法，从而提高对FH患者的护理。
多学科的FH变体管理专家小组亲自会面，并通过频繁的电子邮件和电话会议制定ACMG/AMP指南的LDLR特定修改。通过迭代，试点测试,辩论,和评论，专家达成共识。
对现有ACMG/AMP指南的一致LDLR变体修改包括（1）改变人群频率阈值，(2)函数损失变体类型的划分，（3）功能研究标准规范，（4）共隔离标准规范，(5)仿真预测工具的具体用途和阈值，在其他人中。
建立这些指南作为临床实验室设置的新标准将导致更多的证据，全球LDLR变体分类的统一方法，从而提高对FH患者的护理。
