rs28942085 — LDLR LDLR Y828C (J.D. mutation)

LDLR Y828C — When the LDL Receptor Gets Stuck Outside the Door

The LDL receptor (LDLR)¹¹ LDL receptor (LDLR)
The LDLR gene encodes a cell-surface receptor that removes LDL particles from the bloodstream by binding them and pulling them into the cell for processing is the primary gatekeeper of blood cholesterol. Every cell that needs cholesterol displays LDLR on its surface; the liver uses it most heavily to clear LDL from circulation. When LDLR is absent or non-functional, LDL-C accumulates — a condition called familial hypercholesterolemia (FH).

The Y828C variant (rs28942085) is the historically important "J.D. mutation" — one of the first LDLR variants to be fully characterized at the protein level. It is caused by an A→G change at codon 828, substituting tyrosine with cysteine (p.Tyr828Cys). A second alternate allele (A→C, p.Tyr828Ser) also exists at this position and is classified as likely pathogenic.

The Mechanism

Normal LDLR internalization depends on a tyrosine-based coated-pit targeting signal²² coated-pit targeting signal
Coated pits are specialized regions of the plasma membrane coated with clathrin protein that pinch off to form endosomes, carrying receptor-bound cargo into the cell in the cytoplasmic tail of the receptor. In 1986, Davis et al.³³ Davis et al.
Davis CG et al. The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell, 1986 showed that the Y828C substitution at residue 807 of the mature protein (now numbered 828 in the full pre-protein sequence) destroys this signal. The mutant receptor binds LDL normally but is distributed diffusely across the cell surface instead of concentrating in coated pits. It cannot be efficiently endocytosed, so LDL remains in the bloodstream.

The result is a receptor that is present but functionally paralysed at the final step of lipid uptake. Heterozygous carriers produce one defective receptor copy and one normal copy, giving roughly 50% of normal LDLR activity — enough to cause persistent LDL-C elevation. Homozygous carriers have near-complete loss of LDLR function.

The Evidence

This specific variant has been classified as Pathogenic/Likely pathogenic by five independent submitters in ClinVar (VCV000003893, 2-star review status), including functional studies in fibroblasts and CHO cells from the University of São Paulo and clinical testing data from Revvity Omics.

At the disease level, the clinical burden of FH is well established. Henderson et al. 2016⁴⁴ Henderson et al. 2016
Henderson et al. The genetics and screening of familial hypercholesterolaemia. J Biomed Sci, 2016 confirmed that FH affects approximately 1 in 250 people globally, though the majority remain undiagnosed. Heterozygous FH produces LDL-C typically >190 mg/dL (untreated mean ~243 mg/dL in clinical cohorts), while homozygous FH drives LDL-C above 500 mg/dL with cardiovascular events in childhood.

Long-term cardiovascular risk data from Kjærgaard et al. 2017⁵⁵ Kjærgaard et al. 2017
Kjærgaard et al. Long-term cardiovascular risk in heterozygous familial hypercholesterolemia relatives identified by cascade screening. J Am Heart Assoc, 2017 following 220 relatives from cascade screening for over 20 years found that LDLR mutation carriers had a hazard ratio of 1.94 (95% CI 1.14–3.31) for major cardiovascular events compared with non-carrying relatives — even though 89% of carriers were taking statins throughout follow-up.

Practical Actions

Heterozygous FH is highly treatable. High-intensity statins (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) reduce LDL-C by 50–55%; most heterozygous carriers can reach guideline targets with a statin plus ezetimibe. Carriers who cannot achieve adequate LDL-C reduction with maximal-dose statins and ezetimibe are candidates for PCSK9 inhibitors (evolocumab, alirocumab), which reduce LDL-C by a further 50–60% on top of statin therapy.

Saturated fat restriction (below 7% of total calories) and avoidance of trans fats complement medical therapy but cannot substitute for it — dietary changes alone produce only modest reductions (typically 10–20% at most) in LDL-C when the underlying receptor defect remains.

Cascade screening — testing all first- and second-degree relatives of a confirmed carrier — is the most cost-effective strategy for identifying undiagnosed FH and is recommended by all major cardiology guidelines.

Interactions

FH severity is modulated by other lipid-pathway variants. Concurrent APOE4 (rs429358) worsens LDL-C elevation because APOE4 particles are cleared less efficiently even through intact receptors. APOB pathogenic variants (e.g. rs5742904, familial defective ApoB) cause a clinically similar phenotype and should be excluded when LDLR sequencing is negative. Carriers of two LDLR pathogenic alleles (homozygous FH) or compound heterozygotes with one LDLR and one APOB pathogenic allele present with much more severe disease (LDL-C

400–500 mg/dL) and require LDL apheresis in addition to maximal pharmacotherapy.