rs28942084 — LDLR LDLR Pro685Leu

Pathogenic LDLR missense variant in the EGF precursor domain causing familial hypercholesterolemia with severely elevated LDL-C and early cardiovascular disease

See your personal result for LDLR

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

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.

Nutrient Interactions

saturated fat altered_metabolism
dietary cholesterol altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

No LDLR Pro685Leu — normal LDL receptor function

You do not carry the Pro685Leu pathogenic variant in LDLR. This is the common genotype, present in the vast majority of people (>99.99%). Your LDL receptor function is not impaired by this variant, and you do not have genetically elevated LDL cholesterol from this cause.

CT Heterozygous FH High Risk

One Pro685Leu copy — familial hypercholesterolemia

The Pro685Leu substitution causes defective LDLR processing in the endoplasmic reticulum: the precursor receptor matures more slowly, less of it reaches the cell surface, and the receptor that does arrive binds LDL with reduced affinity. Functional assays show 10–30% of normal LDLR activity — a severe impairment for a single heterozygous variant.

Over 200 individuals with this exact variant have been reported in the FH literature, across populations in Japan, China, India, Zambia, Italy, and Europe. The variant is classified Pathogenic by 39 independent submitters to ClinVar with no conflicting interpretations — one of the more consistently classified LDLR variants in the database.

High-intensity statins (atorvastatin 40–80 mg, rosuvastatin 20–40 mg) reduce LDL-C by 50–60%. Adding ezetimibe typically yields another 20–25%. PCSK9 inhibitors (alirocumab, evolocumab) can provide a further 50–60% reduction on top of statin + ezetimibe, but response varies with residual LDLR activity — monitor LDL-C response at 3 months post-initiation.

All first-degree relatives (parents, siblings, children) have a 50% chance of carrying this variant and should be offered genetic testing and a lipid panel immediately.

TT Homozygous FH Homozygous

Two Pro685Leu copies — homozygous familial hypercholesterolemia

Homozygous Pro685Leu is extraordinarily rare — only a handful of cases have been documented in the literature, including one in a large French FH database. With 10–30% residual LDLR activity in heterozygotes, homozygotes have even less functional receptor, though compound heterozygosity with another LDLR variant (one Pro685Leu allele + one different LDLR pathogenic allele) is more common than true homozygosity.

PCSK9 inhibitor response in HoFH is highly variable and depends on residual LDL receptor activity. Patients with receptor-negative mutations (0% activity) may show no response to PCSK9 inhibitors because these drugs work by preventing PCSK9-mediated receptor degradation — if there is no functional receptor to protect, the drug has nothing to preserve.

LDL apheresis (mechanically filtering LDL from the blood every 1–2 weeks) is frequently required for HoFH when pharmaceutical therapy is inadequate. Novel agents including evinacumab (ANGPTL3 inhibitor, PCSK9-independent mechanism) and lomitapide (MTP inhibitor, reduces VLDL/LDL production) are approved specifically for HoFH.