Adaptation of ACMG/AMP guidelines for standardized variant interpretation in familial hypercholesterolemia

Background: The successes of clinical genetics rely on accurate DNA variant interpretation for the purpose of informing diagnosis and treatment; However, this practice is often rudimentary and differs among diagnostic laboratories, leading to inconsistencies in pathogenicity classification: In response, the Clinical Genome (ClinGen) Resource consortium approves expert panels to recommend disease-specific guidelines to achieve evidence-based, standardized variant curation practice.The ClinGen Consortium is funded by the NHGRI, in conjunction with additional funding from the NICHD and NCI, through the following grants and contracts: 1U41HG006834-01A1, 1U01HG007437-01, 1U01HG007436-01, and HHSN261200800001E.N/

ClinVar database of global familial hypercholesterolemia-associated DNA variants

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.The ClinGen consortium is funded by the National Human Genome Research Institute of the National Institutes of Health through the following grants and contracts: U41HG006834, U41HG009649, U41HG009650, U01HG007436, and U01HG007437.info:eu-repo/semantics/publishedVersio

Familial hypercholesterolemiaassociated variants in ClinVar

Familial Hypercholesterolemia (FH): Lipid metabolism autosomal dominant condition; Patients present elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) values since birth - elevated cardiovascular risk if untreated; High heterozygote prevalence (1/250-500); Homozygous rare (1/300 000-1 000 000); Caused by pathogenic variants in LDLR (>90%), APOB (5-10%) and PCSK9 (1-3%) genes.N/