Chora, Joana RitaLacocca, Michael A.Elnagheeb, MarwaKullo, Iftikhar J.Bourbon, Mafaldaon behalf of the ClinGen FH VCEP2024-01-242024-01-242023-07http://hdl.handle.net/10400.18/8967Familial hypercholesterolemia (FH) is the most common monogenic disorder of lipid metabolism associated with increased cardiovascular risk. FH is caused by pathogenic variants in three main FH genes, of which LDLR is the most frequent. Genetic testing can confirm the clinical diagnosis, but there are currently over 3700 different LDLR variants deposited in ClinVar. In 2022 the Clinical Genome Resource FH Variant Curation Expert Panel (VCEP) recommendations to classify LDLR variants were published. Here, we present the results of the first ten rounds of LDLR variant classification by the FH VCEP. The FH VCEP is currently composed of 12 reviewers, 19 curators, and 10 associated laboratories. Training of biocurators started in August/2021, sustained curation in November/2021, and the most recent round (10th) will end in June/2023. Variants with conflicting classifications in ClinVar and other variants in the same codon (required to properly classify variants) are being prioritized. The FH VCEP preparation team is composed of one alternating curator that uploads de-identified case data sent from associated labs, and one dedicated curator that screens and uploads published papers with functional studies into ClinGen’s Variant Curation Interface (VCI) prior to the curation round. Each variant is assessed using the VCI independently by two curators or one senior curator and approved by three reviewers before being officially published to the Evidence Repository and ClinVar. Once we complete our first ten curation rounds, we will have evaluated 451 LDLR variants: 25 with previous ClinVar review status of no stars (criteria not provided), 333 with one-star (conflicting and single submitter) and 93 with two-stars (multiple submitters, no conflicts). Prior ClinVar classifications were 246 conflicting, 148 Pathogenic/Likely pathogenic (P/LP), 45 Uncertain Significance (VUS), 10 Benign/Likely benign (B/LB) and 2 not provided, totalling only 35% of variants with definite classifications. Currently, 231 variants are published in ClinVar at three-star status, 85 are approved and in the process of being published, 64 are nearly approved and 71 are under evaluation. Among the 374 variants already with an FH VCEP classification, 157 were classified as P/LP, 186 as VUS, 24 as B/LB and only 7 remained conflicting, improving the number of definite classifications to 48% and decreasing the number of conflicting classifications by ~35-fold. Accurate genetic diagnosis relies on correct variant interpretation. FH VCEP guidelines significantly decrease conflicting classifications and provide expert-level consensus data that will facilitate genetic diagnosis, ultimately improving patient management and prognosis.engFamilial HypercholesterolemiaVariant CurationVariant ClassificationClinGenDoenças Cardio e Cérebro-vascularesconference object