rs28942084 — LDLR LDLR Pro685Leu

LDLR Pro685Leu — A Pathogenic Familial Hypercholesterolemia Mutation

The LDL receptor (LDLR) is the liver's primary mechanism for clearing low-density lipoprotein¹¹ low-density lipoprotein
LDL cholesterol — the primary carrier of cholesterol in blood, often called "bad cholesterol" because accumulation in arteries drives atherosclerosis from the bloodstream. Each hepatocyte displays roughly 50,000 LDL receptors that continuously cycle between the cell surface and endosomes, capturing LDL particles and internalizing them for degradation. When LDLR function is impaired by even one pathogenic variant, LDL-C accumulates in the blood from birth, silently damaging arteries for decades.

The Pro685Leu variant (c.2054C>T) is a well-characterized pathogenic mutation found in over 200 individuals with familial hypercholesterolemia across multiple ethnic groups — including populations in Japan, China, India, Zambia, Italy, and European cohorts — earning alternative names FH Zambia, FH Gujerat, FH Frosinone-1, and FH Kanazawa-2. Its worldwide distribution and consistent pathogenicity make it one of the more instructive examples of the global burden of monogenic FH.

The Mechanism

Pro685 sits in the EGF-precursor homology domain of the LDLR, a calcium-dependent structural region²² calcium-dependent structural region
The EGF precursor homology domain (also called the β-propeller domain) coordinates calcium ions that are essential for receptor recycling after LDL release in the acidic endosome essential for receptor recycling after each endocytic cycle. Proline at this position is highly conserved across vertebrate species, and its replacement with leucine disrupts the local protein conformation.

The functional consequence is a combined Class II/III defect: the precursor form of the mutant receptor³³ the precursor form of the mutant receptor
Normal LDLR is synthesized in the endoplasmic reticulum as a ~120 kDa precursor, processed to a mature ~160 kDa glycoprotein, and trafficked to the cell surface in approximately 45 minutes. The Pro685Leu variant slows this maturation and reduces surface expression. is converted to the mature form more slowly than normal, and the receptor that does reach the cell surface binds LDL with reduced affinity. Functional assays consistently demonstrate 10–30% of normal LDLR activity. Five of five in silico prediction tools (SIFT, PolyPhen-2, REVEL score 0.883, etc.) independently rate the substitution as deleterious.

Heterozygous carriers have approximately half the normal hepatic LDL receptor capacity, producing the classic FH phenotype. Rare homozygotes (both LDLR alleles affected) face near-complete loss of LDL clearance, causing extremely severe hypercholesterolemia with LDL-C often exceeding 500 mg/dL.

The Evidence

The landmark Rotterdam cohort study⁴⁴ landmark Rotterdam cohort study
Versmissen et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ, 2008 of 1,950 genetically confirmed FH patients (mean 8.5 years of follow-up) found that statin therapy reduced the cardiovascular event rate by 76% (HR 0.24, 95% CI 0.18–0.30). Treated patients achieved LDL-C reductions of 44–49% with standard statin doses, bringing absolute cardiovascular event rates (11/1,000 person-years) close to those of the general population.

The Pro685Leu variant specifically was identified in two Chinese FH pedigrees⁵⁵ two Chinese FH pedigrees
Yao et al. Identification of LDLR mutations in two Chinese pedigrees with familial hypercholesterolemia. J Pediatr Endocrinol Metab, 2012 including a compound heterozygous child with severe FH. Across 39 ClinVar submissions from major diagnostic laboratories (Invitae, GeneDx, Mayo Clinic Laboratories, Quest Diagnostics, ARUP Laboratories, Color Diagnostics), zero submissions conflict with a Pathogenic classification. ACMG/AMP criteria applied include PS4 (prevalence in affected individuals), PP1_Strong (co-segregation with disease), PM2 (absent from controls), and PS3_Supporting (functional studies).

Practical Actions

Single-copy (heterozygous) carriers should expect untreated LDL-C in the 190–400 mg/dL range. High-intensity statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) is the first-line intervention and can reduce LDL-C by 50–60%. Ezetimibe (10 mg daily) added to a statin provides an additional 20–25% LDL-C reduction through complementary mechanism (intestinal cholesterol absorption inhibition). If LDL-C targets are not met on statin + ezetimibe, PCSK9 inhibitors (alirocumab, evolocumab) add another 50–60% on top of background therapy — though their efficacy depends on residual LDL receptor function, so response monitoring is important.

Cascade screening of all first-degree relatives is recommended immediately on diagnosis: each first-degree relative has a 50% probability of carrying the same variant and will have been accumulating LDL-driven atherosclerosis since birth without knowing it. Children of carriers should be tested by age 8–10.

Interactions

The cardiovascular burden of LDLR Pro685Leu compounds with APOE genotype. APOE E4 carriers (rs429358 CT or CC) already have impaired LDL clearance through a separate mechanism; those who also carry an LDLR pathogenic variant face additive LDL elevation and may require more aggressive lipid-lowering therapy. Similarly, PCSK9 gain-of-function variants (which increase LDL receptor degradation) can worsen the FH phenotype.