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.

Academic Medical Center Erasmus University Rotterdam Netherlands

Ambry Genetics Aliso Viejo CA

Bristol Genetics Laboratory North Bristol NHS Trust Bristol United Kingdom

Centre for Cardiovascular Genetics Institute of Cardiovascular Science University College London London United Kingdom

Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic; Faculty of Medicine Masaryk University Brno Czech Republic

Centre of Molecular Biology and Gene Therapy University Hospital Brno Brno Czech Republic

Color Health Inc Burlingame CA

Department of Clinical Biochemistry PathWest Laboratory Medicine WA Royal Perth Hospital and Fiona Stanley Hospital Network University of Western Australia Perth Western Australia Australia

Department of Genetics School of Medicine University of North Carolina at Chapel Hill Chapel Hill NC

Department of Health Promotion and Prevention of Noncommunicable Diseases Nacional Institute of Health Dr Ricardo Jorge Lisbon Portugal; BioISI BioSystems and Integrative Sciences Institute Department of Chemistry and Biochemistry Faculty of Sciences University of Lisbon Lisbon Portugal

Department of Medicine Faculty of Medicine The University of British Columbia Vancouver British Columbia Canada

Departments of Biomedical Data Science and Pathology School of Medicine Stanford University Stanford CA; Center for Inherited Cardiovascular Disease Stanford Health Care Stanford University Stanford CA

Departments of Biomedical Data Science and Pathology School of Medicine Stanford University Stanford CA; Department of Paediatric Laboratory Medicine The Hospital for Sick Children Toronto Ontario Canada

Division of Cardiovascular Medicine Stanford Cardiovascular Institute Prevention Research Center and Diabetes Research Center School of Medicine Stanford University Stanford CA; FH Foundation Pasadena CA

GeneDx Inc Gaithersburg MD

Genomics England London United Kingdom

Laboratory of Genetics and Molecular Cardiology Institute of the Hearth Faculty of Medicine São Paulo University São Paulo Brazil

Robarts Research Institute Schulich School of Medicine and Dentistry Western University London Ontario Canada

University Hospitals Pitié Salpêtrière Charles Foix Molecular and Chromosomal Genetics Center Obesity and Dyslipidemia Genetics Unit Sorbonne University Paris France

References provided by Crossref.org

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance