Available online 1 December 2025

SCARB1 was sequenced in 96 extreme-HDL-C subjects; 25 variants identified.

Novel c.-177G>T promoter and missense p.(Thr118Ser) were described.

p.(Thr118Ser) and p.(Thr378Met) co-segregate with high HDL-C.

p.(Thr378Met) variant impairs SR-B1–mediated HDL uptake in vitro.

Rare variants in SCARB1, which encodes the HDL receptor SR-B1, are hypothesized to drive unexplained extreme levels of plasma high-density-lipoprotein cholesterol (HDL-C).

We sequenced and phenotypically correlated SCARB1 by analyzing individuals with extreme HDL-C levels and characterizing the functional consequences of rare identified variants.

SCARB1 was Sanger-sequenced in 96 unrelated participants with extreme HDL-C levels. Clinical, biochemical, and anthropometric data were compared between groups. Bioinformatic tools were used to predict the functional impact of all detected variants. Familial analyses of predicted damaging in silico or not previously described variants was assessed, and HDL uptake was quantified by flow cytometry in HEK293 cells expressing rare SCARB1 variants showing a suggestive pattern of familial segregation.

Compared with the high-HDL-C group, low-HDL-C subjects exhibited lower LDL-C and total cholesterol but higher triglycerides, higher body mass index, and a greater frequency of atherosclerotic cardiovascular disease events. Twenty-five SCARB1 variants were identified; four of them, c.-177G>T, p.(Thr118Ser), c.843-982G>A and p.(Thr378Met), were predicted to be deleterious. The missense changes p.(Thr118Ser) and p.(Thr378Met) showed a suggestive pattern of segregation with high HDL-C in available pedigrees. Cells expressing p.(Thr378Met) SCARB1 variant showed a reduction in HDL uptake versus wild-type.

Rare predicted damaging in silico variant in SCARB1, p.(Thr378Met), impair SR-B1-mediated HDL uptake and associate with high HDL-C levels, highlighting SCARB1 as a candidate gene for genetic screening in dyslipidaemic patients.

Extreme HDL-C

SCARB1 sequencing

SR-B1

ASCVD

atherosclerotic cardiovascular disease

coronary arterial disease

gamma-glutamyl transferase

glutamic-pyruvic transaminase

High-density lipoproteins

cholesterol carried by high-density lipoprotein

Hospital Universitario Miguel Servet

Low-density lipoproteins

cholesterol carried by Low-density lipoprotein

reverse cholesterol transport

scavenger receptor class B type 1

very low-density lipoproteins

© 2025 Published by Elsevier Inc. on behalf of National Lipid Association.