Lipoprotein Lipase: Structure, Function, and Genetic Variation

Biallelic rare pathogenic loss-of-function (LOF) variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome (FCS). Heterozygosity for these same variants is associated with a highly variable plasma triglyceride (TG) phenotype ranging from normal to severe hypertriglyceridemia (HTG), with longitudinal variation in phenotype severity seen often in a given carrier. Here, we provide an updated overview of genetic variation in LPL in the context of HTG, with a focus on disease-causing and/or disease-associated variants. We provide a curated list of 300 disease-causing variants discovered in LPL, as well as an exon-by-exon breakdown of the LPL gene and protein, highlighting the impact of variants and the various functional residues of domains of the LPL protein. We also provide a curated list of variants of unknown or uncertain significance, many of which may be upgraded to pathogenic/likely pathogenic classification should an additional case and/or segregation data be reported. Finally, we also review the association between benign/likely benign variants in LPL, many of which are common polymorphisms, and the TG phenotype.