A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity.

•We found a heterozygous variant OSBPL1A p.C39X in subjects with high-density-lipoprotein cholesterol (HDL-C) <1st percentile.•Sera of the carriers displayed a reduced capacity to act as acceptors for cholesterol efflux.•Fibroblasts from a p.C39X carrier showed reduced cholesterol efflux to lipid-free apoA-I.•GFP-OSBPL1A-39X protein remained cytosolic and failed to bind Rab7, the receptor of OSBPL1A on late endosomes/lysosomes.•This is the first report on a human OSBPL1A mutation, and suggests that rare OSBPL mutations may contribute to dyslipidemias.