Author(s):
Chora, Joana R. ; Iacocca, Michael A. ; Tichý, Lukáš ; Wand, Hannah ; Kurtz, C. Lisa ; Zimmermann, Heather ; Leon, Annette ; Williams, Maggie ; Humphries, Steve E. ; Hooper, Amanda J. ; Trinder, Mark ; Brunham, Liam R. ; Costa Pereira, Alexandre ; Jannes, Cinthia E. ; Chen, Margaret ; Chonis, Jessica ; Wang, Jian ; Kim, Serra ; Johnston, Tami ; Soucek, Premysl ; Kramarek, Michal ; Leigh, Sarah E. ; Carrié, Alain ; Sijbrands, Eric J. ; Hegele, Robert A. ; Freiberger, Tomáš ; Knowles, Joshua W. ; Bourbon, Mafalda ; ClinGen Familial Hypercholesterolemia Expert Panel
Date: 2022
Persistent ID: http://hdl.handle.net/10400.18/8289
Origin: Repositório Científico do Instituto Nacional de Saúde
Subject(s): ACMG/AMP; ClinGen; Familial Hypercholesterolemia; LDLR; Variant Classification; Doenças Cardio e Cérebro-vasculares; Colesterol; Hipercolesterolemia Familiar
Description
Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
