rs137943601 — LDLR LDLR E408* (Glu408Ter)

LDLR E408* — When the LDL Receptor Is Silenced

The low-density lipoprotein receptor (LDLR)¹¹ low-density lipoprotein receptor (LDLR)
a transmembrane protein on liver and other cells that binds LDL particles and pulls them out of circulation is the central traffic controller of blood cholesterol. Every cell that needs cholesterol expresses LDLR; liver cells express the most, and it is there that the majority of circulating LDL-cholesterol is cleared from the bloodstream. When LDLR is silenced by a pathogenic mutation, LDL accumulates unchecked — the primary cause of familial hypercholesterolemia (FH)²² familial hypercholesterolemia (FH)
an inherited condition characterized by lifelong severely elevated LDL-cholesterol and premature atherosclerotic cardiovascular disease.

This position (c.1222, codon 408) is a multi-allelic hotspot in LDLR. The most severe allele — the T allele profiled here — introduces a premature stop codon at glutamic acid 408 (p.Glu408Ter, also written E408*), truncating the protein and completely abolishing receptor function. Two other alleles exist at the same position: G>C (p.Glu408Gln, missense, uncertain significance per ClinGen expert panel) and G>A (p.Glu408Lys, missense, associated with hypercholesterolemia in case series). All three are absent from large population databases, confirming their ultra-rare pathogenic status.

The Mechanism

The Glu408Ter nonsense mutation introduces a TGA stop codon at position 408 of the 860-amino-acid LDLR protein, midway through the epidermal-growth-factor (EGF) precursor homology domain³³ epidermal-growth-factor (EGF) precursor homology domain
a region required for receptor recycling after LDL delivery; without it, receptors cannot release LDL in the endosome and return to the cell surface. The truncated mRNA is typically degraded by nonsense-mediated decay, meaning the cell produces essentially no functional LDLR protein from this allele.

Tabet et al. 2026 (Science)⁴⁴ Tabet et al. 2026 (Science) experimentally tested nearly all possible LDLR coding variants, generating a comprehensive sequence-function map. Nonsense/stop-gain variants — including all premature stop codons in the receptor's extracellular and transmembrane domains — uniformly produced zero detectable cell-surface LDLR expression and zero LDL uptake, consistent with complete loss of function. This classification as a Class 1 (synthesis-null) or Class 5 (no LDL uptake) variant places it among the most severe LDLR mutation classes.

Heterozygous carriers have one functional LDLR allele and one null allele, reducing receptor density on hepatocytes by approximately 50%. This halved clearance capacity produces the hallmark heterozygous FH phenotype: LDL-cholesterol typically in the range of 190–400 mg/dL (normal: below 100 mg/dL in adults at low cardiovascular risk). Homozygous carriers (two null alleles) have essentially no functional LDLR and LDL-C levels exceeding 500 mg/dL, with xanthomas, corneal arcus, and coronary artery disease appearing in childhood.

The Evidence

Marduel et al. 2010 (Human Mutation)⁵⁵ Marduel et al. 2010 (Human Mutation) surveyed the molecular spectrum of autosomal dominant hypercholesterolemia in 1,358 French probands, identifying 391 distinct LDLR mutation events. Nonsense mutations — the class to which Glu408Ter belongs — accounted for 11.3% of all unique pathogenic events, consistently associated with the most severe LDL-C elevations and the highest cardiovascular disease penetrance.

The ClinVar expert panel classification for the nonsense allele is Pathogenic (VCV001371905), submitted by Labcorp Genetics with functional evidence that the stop-gain creates an absent or disrupted protein product. Loss-of-function LDLR variants are among the most robustly validated pathogenic variant classes in human genetics, with over 1,700 disease-causing LDLR variants catalogued in the ClinVar/ClinGen FH database.

Epidemiologically, heterozygous FH affects approximately 1 in 200–250 individuals globally, making it one of the most common inherited metabolic disorders. Without treatment, heterozygous men with FH face a 50% risk of coronary heart disease by age 50; women by age 60. The GeneReviews FH overview⁶⁶ GeneReviews FH overview documents that untreated adults with FH have a coronary heart disease risk 10- to 20-fold higher than age-matched controls.

Practical Actions

The evidence for statin therapy in FH is unambiguous. High-intensity statins (atorvastatin 40–80 mg, rosuvastatin 20–40 mg) reduce LDL-C by 50–60% and dramatically reduce cardiovascular event rates in FH patients. For carriers who cannot achieve LDL-C targets on statins alone — a common finding given the severity of the receptor defect — combination therapy with ezetimibe (which blocks intestinal cholesterol absorption) and/or PCSK9 inhibitors (evolocumab, alirocumab) can achieve further 50–70% reductions on top of statins. The RNA-targeted therapy inclisiran offers an alternative for those requiring additional LDL-C lowering.

Dietary modification is an important but insufficient standalone intervention in LDLR null carriers. Reducing saturated fat intake to below 7% of total calories and limiting dietary cholesterol decreases LDL-C synthesis burden, but because the fundamental defect is clearance failure rather than overproduction, dietary changes alone rarely bring LDL-C into the target range. Medications are required.

Cascade screening — testing first-degree relatives — is the single most cost-effective cardiovascular prevention intervention for FH families. Each affected parent has a 50% chance of passing this autosomal dominant variant to each child.

Interactions

LDLR null variants have a well-documented interaction with APOE genotype. rs429358⁷⁷ rs429358 (APOE ε4) independently impairs LDL clearance via a separate mechanism — APOE ε4 binds LDL receptors with reduced efficiency compared to APOE ε3. Carrying both an LDLR null allele and APOE ε4 compounds the LDL-clearance defect beyond the sum of either variant alone, and such individuals may have more severely elevated LDL-C and earlier cardiovascular disease onset than predicted from the LDLR variant alone.

The PCSK9 gene (rs11591147, rs562556) encodes a protein that degrades LDLR. Loss-of-function PCSK9 variants that increase LDLR surface density — naturally reducing LDL-C — can partially mitigate the severity of heterozygous FH. Conversely, PCSK9 gain-of-function variants (which further reduce LDLR) would compound the LDLR null allele's effects. These interactions explain why PCSK9 inhibitor drugs are particularly effective in LDLR-deficient patients.