rs763625913 — LDLR Q770* (c.2308C>T)

LDLR Q770* — When the LDL Receptor Stops Working

The LDLR gene¹¹ LDLR gene
encodes the LDL receptor, a cell-surface protein that captures and removes LDL cholesterol from the bloodstream by binding apolipoprotein B-100 on LDL particles and shuttling them into cells for degradation. Without functional LDL receptors, circulating LDL accumulates relentlessly from birth — a condition called familial hypercholesterolemia²² familial hypercholesterolemia
the most common serious monogenic disorder, affecting ~1 in 250 people globally in its heterozygous form.

The rs763625913 variant (c.2308C>T) creates a premature stop codon at position 770 of the LDLR protein, producing a truncated, non-functional receptor. This is a receptor-negative mutation³³ receptor-negative mutation
the receptor is either not made or completely unable to bind LDL, the most severe functional class of LDLR variants. ClinVar classifies it Pathogenic for hypercholesterolemia, familial type 1⁴⁴ hypercholesterolemia, familial type 1
the autosomal dominant form caused by LDLR mutations.

The Mechanism

A nonsense mutation⁵⁵ nonsense mutation
a single DNA base change that replaces an amino acid codon with a stop codon, terminating protein synthesis prematurely at codon 770 (Gln→stop) removes the last 89 amino acids of the mature LDLR protein, which include critical domains required for receptor recycling. The truncated receptor cannot be properly expressed on the hepatocyte surface. With one defective copy (heterozygous state), approximately half the normal number of LDL receptors are present, reducing LDL clearance by ~50% and causing LDL-C to accumulate to 190–300 mg/dL⁶⁶ LDL-C to accumulate to 190–300 mg/dL
roughly 2–3× the normal range from childhood onward. The endogenous cholesterol synthesis pathway⁷⁷ endogenous cholesterol synthesis pathway
the liver continues producing cholesterol but cannot recycle the LDL fraction efficiently through the receptor pathway, compounding the problem.

The Evidence

Pathogenic LDLR nonsense and frameshift variants — the class to which Q770* belongs — are classified as receptor-negative mutations⁸⁸ receptor-negative mutations
producing no functional receptor activity. Bertolini et al. in a multicenter Italian cohort of 282 FH patients⁹⁹ Bertolini et al. in a multicenter Italian cohort of 282 FH patients
clustering mutations by regional ancestry and functional class showed that receptor-negative carriers had 18% higher LDL-C, 2.6-fold more coronary artery disease, and 2-fold more tendon xanthomas than receptor-defective carriers — confirming that complete receptor abolition is the most severe functional consequence of LDLR mutation.

Without treatment, untreated heterozygous FH carries approximately 50% cumulative coronary event risk by age 50 in men and 30% by age 60 in women¹⁰¹⁰ 50% cumulative coronary event risk by age 50 in men and 30% by age 60 in women
based on natural history registry data from the pre-statin era. The overall coronary disease excess is estimated at up to 13-fold compared to the general population¹¹¹¹ up to 13-fold compared to the general population
European Atherosclerosis Society consensus statement on FH. Critically, this risk is dramatically modifiable: high-intensity statin therapy initiated early reduces cardiovascular events by 50–80% and narrows the life expectancy gap with unaffected relatives.

This variant is extremely rare (one observation across 595,462 gnomAD exome alleles), consistent with strong purifying selection — individuals carrying it face severely elevated cardiovascular risk from birth, and reproductive fitness is reduced. Most carriers identified in clinical practice are ascertained through cascade screening after a proband is diagnosed with premature CAD or markedly elevated LDL-C.

Practical Actions

Carrying this variant is a medical diagnosis equivalent to clinically confirmed FH. The first priority is confirming the lipid phenotype with a fasting lipid panel — LDL-C is typically 190–300 mg/dL in untreated heterozygotes. High-intensity statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily) should be initiated regardless of age in adults, and as early as age 8–10 in affected children. The LDL-C target is <100 mg/dL for most carriers, or <70 mg/dL if coronary artery disease is already present. Because receptor-negative variants produce a more severe phenotype than receptor-defective variants, reaching these targets often requires combination therapy: high-intensity statin + ezetimibe 10 mg, and frequently a PCSK9 inhibitor¹²¹² PCSK9 inhibitor
evolocumab or alirocumab, which increase LDL receptor expression from the remaining functional allele by preventing receptor degradation.

Because FH follows autosomal dominant inheritance, every first-degree relative has a 50% chance of carrying this variant. Cascade genetic testing or LDL-C screening in parents, siblings, and children is recommended as soon as the proband is identified — early intervention in childhood prevents decades of LDL-C-driven atherosclerosis.

Interactions

This variant interacts with other cholesterol pathway variants. Carriers who also carry a PCSK9 gain-of-function variant¹³¹³ PCSK9 gain-of-function variant
e.g. rs28942080 D374Y face compounded LDL receptor dysfunction: PCSK9 rapidly degrades the residual functional LDLR protein, making pharmacologic PCSK9 inhibition especially important. Conversely, carriers of PCSK9 loss-of-function variants¹⁴¹⁴ PCSK9 loss-of-function variants
such as rs28362261 Y142X may show attenuated LDL elevation even with one defective LDLR allele, because more of the functional receptor is preserved.

Lifestyle factors modify penetrance: obesity, insulin resistance, and hypothyroidism all further impair LDL clearance and worsen the phenotype, while intensive dietary fat restriction (saturated fat below 7% of calories) can modestly reduce LDL-C by 10–15% on top of pharmacotherapy. These lifestyle modifications do not substitute for statins in this context but can assist in reaching LDL targets.