Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.

Academic Medical Center University of Amsterdam Amsterdam Netherlands

BioISI University of Lisbon Lisbon Portugal

Ceitec and Medical Faculty Masaryk University Brno London

Center for Inherited Cardiovascular Disease Stanford University Palo Alto California

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

Centre for Cardiovascular Genetics University College of London London United Kingdom

Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic

CNRS CHU Lille UMR 8199 Integrative Genomics and Metabolic Diseases Modeling University of Lille Lille France

Color Genomics Burlingame California

Department of Genetics University of North Carolina Chapel Hill North Carolina

FH Foundation Pasadena California

Fundacion Hipercolesterolemia Familiar Madrid Spain

Genomics England London United Kingdom

Harvard Medical School Harvard University Boston Massachusetts

Hôpitaux Universitaires Pitié Salpêtrière Charles Foix Molecular and Chromosomal Genetics Center Obesity and Dyslipidemia Genetics Unit Assistance Publique Hôpitaux de Paris Paris France

Inserm Institute of Cardiometabolism and Nutrition Hôpital de la Pitié Sorbonne Université Paris France

Instituto do Coração São Paulo Brazil

Instituto Nacional de Saúde Doutor Ricardo Jorge Lisbon Portugal

Invitae Corporation San Francisco California

PathWest Laboratory Medicine University of Western Australia Perth Australia

Robarts Research Institute Western University London Ontario Canada

University Medical Center Erasmus University Rotterdam Netherlands

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Genetics of Familial Hypercholesterolemia: New Insights