rs730882094 — LDLR Asn316Ser (N316S)

LDLR Asn316Ser — When the LDL-Clearing Machinery Breaks Down

Every cell in your body needs cholesterol to build membranes and synthesize hormones. To keep blood LDL from accumulating, the LDLR gene¹¹ LDLR gene
Low-density lipoprotein receptor: a cell-surface protein that captures LDL particles circulating in blood and pulls them into cells for degradation, removing them from the bloodstream encodes a receptor that acts like a molecular claw — binding LDL particles at the cell surface, pulling them inside, releasing the LDL into the lysosome for processing, and then recycling back to the surface to repeat the cycle. rs730882094 introduces a single amino acid change at position 316 of this receptor protein — swapping asparagine for serine — within one of the receptor's critical EGF-like repeat domains²² EGF-like repeat domains
EGF precursor homology domain: a structural region of the LDLR that enables acid-dependent release of LDL in the endosome and receptor recycling back to the cell surface. Mutations here often impair LDLR biosynthesis, trafficking to the cell surface, or the conformational switch needed for pH-dependent LDL release. The consequence is impaired receptor processing, reduced LDL clearance, and lifelong elevation of LDL cholesterol — the hallmark of familial hypercholesterolemia (FH).

FH is one of the most common inherited metabolic disorders³³ one of the most common inherited metabolic disorders
Familial hypercholesterolemia affects an estimated 1 in 200–250 individuals globally (heterozygous form), yet fewer than 10% are diagnosed or treated in most countries, but LDLR variant–specific entries like Asn316Ser are rare — gnomAD records only 11 G-allele chromosomes among 1.4 million in the exome database (~0.001%). The variant was classified as Likely Pathogenic⁴⁴ classified as Likely Pathogenic
ClinVar VCV000183103: 4 of 6 expert submissions classify this as Likely Pathogenic for familial hypercholesterolemia; 2 classify as Uncertain Significance. The LP classifications come from the British Heart Foundation LDLR-LOVD database, Color Diagnostics, All of Us Research Program (NIH), and Charité Berlin for familial hypercholesterolemia by multiple independent submitters.

The Mechanism

The LDLR protein consists of several domains: an LDL-binding domain at the N-terminus, followed by EGF precursor homology (EGFPH) repeats A, B, and C that control pH-dependent LDL release and receptor recycling. Asn316 sits within EGF-like repeat A (amino acids 315–354), a region enriched for pathogenic LDLR variants⁵⁵ enriched for pathogenic LDLR variants
Functional studies from ClinVar submitter Merck Research Labs show this variant "interferes with protein transport and significantly affects LDLR biosynthesis or turnover," consistent with the known functional role of EGF-A domain asparagines in receptor folding and glycosylation and one where asparagine residues are known to be important for N-linked glycosylation, protein folding, and intracellular trafficking. Substituting serine at position 316 disrupts these interactions, impairing the receptor's maturation and transport to the cell surface.

The result is a reduced number of functional LDL receptors available to clear circulating LDL particles. LDL accumulates in plasma, depositing in arterial walls over decades and driving accelerated atherosclerosis. In untreated FH heterozygotes (carrying one mutant LDLR allele), LDL-C typically runs 2–4× above population norms from birth — a cumulative atherogenic burden that manifests as premature coronary artery disease, often before the fifth decade of life.

The Evidence

The classification of this variant rests on a combination of evidence:

Functional data: Merck Research Labs functional profiling data in ClinVar documents that Asn316Ser "interferes with protein transport and significantly affects LDLR biosynthesis or turnover" — a non-trivial mechanistic finding even if the full study data are unpublished. Computational predictions are conflicting (SIFT: deleterious; PolyPhen-2: benign), which is common for variants in the EGF domain where the structural context matters more than biochemical similarity scores.

Clinical observations: Five heterozygous carriers in one series⁶⁶ Five heterozygous carriers in one series
ClinVar submitter Molecular Genetics Lab, Centre for Cardiovascular Surgery, Czech Republic — observed 5 individuals aged 22–53 with clinical FH features: hypercholesterolemia, xanthelasma, tendon xanthomas, and corneal arcus (for the closely related Asn316Thr variant at the same codon) presented with classic FH clinical features, strengthening the pathogenic case for this codon.

Disease context: Defesche et al.'s landmark 2017 review⁷⁷ Defesche et al.'s landmark 2017 review
Defesche JC et al. Familial hypercholesterolaemia. Nat Rev Dis Primers, 2017 established that untreated FH confers up to a 13-fold increased risk of coronary heart disease compared to the general population, with event risk accumulating silently from childhood. Nordestgaard et al.'s European Atherosclerosis Society consensus⁸⁸ Nordestgaard et al.'s European Atherosclerosis Society consensus
Nordestgaard BG et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. Eur Heart J, 2013 set adult LDL-C targets below 2.5 mmol/L (≈97 mg/dL) for FH patients and below 1.8 mmol/L (≈70 mg/dL) for those with established coronary disease.

The aggregate classification of Likely Pathogenic (rather than Pathogenic) reflects the relatively small number of independent affected families described to date for this specific allele, and conflicting computational predictions. As data accumulate, reclassification to Pathogenic is possible.

Practical Actions

For heterozygous carriers of rs730882094 G, the key priorities are: (1) confirm LDL-C elevation with a fasting lipid panel, (2) initiate high-intensity statin therapy as early as feasible, (3) cascade-test first-degree relatives, and (4) manage all co-occurring cardiovascular risk factors aggressively.

Statins remain the first-line treatment⁹⁹ Statins remain the first-line treatment
High-intensity statins (rosuvastatin 20–40 mg, atorvastatin 40–80 mg) reduce LDL-C by 50–55% as monotherapy. Addition of ezetimibe provides a further 15–20% reduction. PCSK9 inhibitors (evolocumab, alirocumab) achieve an additional 50–60% reduction and are indicated when LDL-C target is not achieved with maximum tolerated statin + ezetimibe for FH. Early treatment reduces lifetime atherosclerotic burden. In FH heterozygotes without other risk factors, treatment targets LDL-C below 2.5 mmol/L (97 mg/dL); in those with existing cardiovascular disease, below 1.8 mmol/L (70 mg/dL).

Interactions

LDLR Asn316Ser interacts with other genetic modifiers of LDL metabolism. APOE genotype (rs429358 / rs7412) modulates LDL levels independently — carriers of APOE ε4 alongside an LDLR variant may have even higher LDL than expected from the LDLR mutation alone. PCSK9 gain-of-function variants (e.g., rs28942453 / PCSK9 D374Y) accelerate LDLR degradation and compound the receptor deficit; PCSK9 loss-of-function variants are protective and may blunt FH severity. APOB variants (e.g., rs121908028 / APOB R3527Q) cause a clinically identical FH phenotype through a different mechanism (impaired LDL particle binding rather than receptor dysfunction). Genetic testing panels for FH routinely screen all three genes simultaneously.