Abstract

DOI:10.1097/MOL.0000000000000584 Familial hypercholesterolaemia is an autosomal dominant disorder of lipid metabolism characterized by elevated levels of LDL-C and increased cardiovascular risk. Although the disorder can be diagnosed based on established clinical criteria, only the genetic diagnosis confirms the clinical suspicion [1 && ]. There are three main genes associated with familial hypercholesterolaemia: LDL receptor (LDLR), responsible for more than 90% of the cases, apolipoprotein B (APOB), responsible for 5–10% of the cases and Proprotein Convertase Subtilisin/ Kexin Type 9 (PCSK9), responsible for up to 3% of the cases. However, reporting of situations where there is an overlap of the familial hypercholesterolaemia phenotype and other conditions is now growing [1 && ]. Much is known about the mutational spectrum of familial hypercholesterolaemia but the lack of functional studies for the great majority of variants [2 & ] compromises the diagnosis. Standardized variant classification algorithms and centralized opensource data sharing is crucial for incorporation of results from rapidly developing sequencing technologies into genomic medicine for improved patient care. Following this line, the Clinical Genome Resource (ClinGen) and ClinVar are working together to improve such aspects. The most updated public database for familial hypercholesterolaemia is now ClinVar reaching 5908 submissions and 2883 unique familial hypercholesterolaemia variants [3 && ]. These numbers increased 18-fold compared with the end of 2015 because of the concerted efforts made by the ClinGen FH Variant Curation Expert Panel and global familial hypercholesterolaemia community to increase submission of familial hypercholesterolaemia-associated variants into ClinVar; which so far reached 30 submitters in 14 different countries and the work is still in progress. As expected, LDLR variants are the most abundant, with 2314 unique variants (80%) when compared with the 353 unique variants (12%) in APOB and 216 (8%) in PCSK9 [3 && ]. However, functional studies were reported only for 334 unique variants and variant classification methods are not standardized, resulting in different variant interpretations [3 && ]. Additionally, in a previous report [4 & ], 50% of all worldwide familial hypercholesterolaemia-associated variants were classified as variants of unknown