Homozygous CETP c.848del deficiency produces extreme HDL-C of 377.2 mg/dL with subclinical atherosclerosis in a 55-year-old woman (J Clin Lipidol 2026)

Extremely elevated high-density lipoprotein cholesterol (HDL-C) does not necessarily confer cardiovascular protection. We report a 55-year-old woman with persistent HDL-C elevation, reaching 377.2 mg/dL, with carotid atherosclerotic plaques and a coronary artery calcium score of 33. Genetic analysis identified a homozygous cholesteryl ester transfer protein (CETP) c.848del, p.(Ser283Leufs*11) frameshift variant and a homozygous scavenger receptor class B member 1 (SCARB1) c.1133C>T, p.(Thr378Met) missense variant. The SCARB1 variant remains a variant of uncertain significance, although its rarity, in silico predictions, and published functional evidence support a potential contribution to the extreme HDL-C phenotype. Because direct HDL functional assays were not performed, the coexistence of extreme HDL-C and subclinical atherosclerosis should not be interpreted as evidence of dysfunctional HDL or a causal relationship. This case highlights the complex relationship between genetically determined extreme HDL-C elevation and cardiovascular phenotype.