ClinVar database of global familial hypercholesterolemia-associated DNA variants.

Iacocca MA1, Chora JR2,3, Carrié A4,5, Freiberger T6,7, Leigh SE8, Defesche JC9, Kurtz CL10, DiStefano MT11, Santos RD12, Humphries SE13, Mata P14, Jannes CE12, Hooper AJ15, Wilemon KA16, Benlian P17, O'Connor R18, Garcia J19, Wand H20, Tichy L21, Sijbrands EJ22, Hegele RA1, Bourbon M2,3, Knowles JW16,20; ClinGen FH Variant Curation Expert Panel.

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Abstract

Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomicmedicine 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.