rs28942083 — LDLR Cys667Tyr

LDLR Cys667Tyr — A Broken LDL Receptor Causing Familial Hypercholesterolemia

Your LDL cholesterol is cleared from the bloodstream primarily by a receptor protein called the LDL receptor (LDLR)¹¹ LDL receptor (LDLR)
A cell-surface protein on liver cells that binds LDL particles and pulls them out of circulation for degradation. Without enough functional LDLR, LDL accumulates in the blood from birth, silently depositing cholesterol in artery walls decades before symptoms appear. The LDLR Cys667Tyr variant is one of over 1,700 known pathogenic mutations in this gene that cause familial hypercholesterolemia (FH)²² familial hypercholesterolemia (FH)
An inherited disorder of LDL cholesterol metabolism; the most common serious Mendelian disease, affecting ~1 in 250 people in its heterozygous form.

The Mechanism

The rs28942083 A allele encodes a missense substitution at position 667 of the LDLR protein — cysteine to tyrosine (p.Cys667Tyr). Cysteine-667 is located in the EGF precursor homology domain³³ EGF precursor homology domain
A domain required for proper protein folding and recycling of the receptor after LDL delivery inside the cell of the receptor. This cysteine normally participates in a critical disulfide bond. When replaced by tyrosine, the bond cannot form, the protein misfolds, and it is retained in the endoplasmic reticulum⁴⁴ retained in the endoplasmic reticulum
The cellular compartment where newly synthesized proteins are folded and quality-checked before being dispatched to the cell surface instead of reaching the liver cell surface.

Functional studies in fibroblasts from a homozygous patient⁵⁵ Functional studies in fibroblasts from a homozygous patient
Leitersdorf et al., J Clin Invest 1990 showed that only 20% of LDLR protein was processed to its mature surface form; independent assays measured residual LDLR activity below 2%. This near-complete loss of function is the molecular basis of the disease phenotype.

The Evidence

FH caused by LDLR loss-of-function mutations is one of the best-characterized genetic disorders in medicine. A 2013 consensus statement from the European Atherosclerosis Society⁶⁶ A 2013 consensus statement from the European Atherosclerosis Society
Nordestgaard et al., Eur Heart J 2013 based on 63,000 individuals established that untreated heterozygous FH carriers face a 22-fold elevated risk of coronary artery disease compared to the general population, with untreated men reaching a 50% probability of a fatal or nonfatal coronary event by age 50 and untreated women by age 60.

Untreated LDL-C in heterozygous FH typically exceeds 190 mg/dL (4.9 mmol/L); homozygous individuals often reach 400–600 mg/dL. Without treatment, xanthomas (cholesterol deposits in tendons and skin) and premature cardiovascular disease are near-universal by the fourth or fifth decade of life.

The p.Cys667Tyr variant is particularly prevalent in French Canadian populations⁷⁷ French Canadian populations
Due to a founder effect tracing to a small founding population in Québec in the 17th century, where it is known as the "FH French Canadian-2" allele and accounts for a substantial fraction of FH cases in that community. The variant has also been identified across European populations in over 40 documented heterozygous individuals.

High-intensity statin therapy (e.g., rosuvastatin 20–40 mg or atorvastatin 40–80 mg) reduces LDL-C by approximately 50%, and registry studies show that treated FH patients have cardiovascular event rates roughly half those of untreated carriers. Many patients require additional agents — ezetimibe (further 20% LDL reduction) or PCSK9 inhibitors such as evolocumab or alirocumab (50–60% additional reduction) — to reach guideline targets.

Practical Actions

Carrying even one copy of this variant is a medical finding that warrants immediate attention from a lipid specialist or cardiologist. The primary intervention is aggressive pharmacological lowering of LDL-C, started as early as possible — ideally in childhood for heterozygous FH — to reduce lifetime arterial cholesterol exposure. Dietary changes that limit saturated fat intake (below 7% of total calories) reduce LDL-C by a further 8–15% and are a meaningful complement to drug therapy but cannot substitute for it.

Cascade screening of first-degree relatives (parents, siblings, children) is essential: heterozygous FH follows autosomal dominant inheritance, so each first-degree relative has a 50% probability of carrying the same variant.

Interactions

The rs28942083 A allele acts dominantly — one copy is sufficient to cause FH. Its severity in heterozygotes can be modulated by variants in other lipid genes:

• PCSK9 rs11591147 (R46L) — Loss-of-function PCSK9 variants partially offset LDLR deficiency by reducing PCSK9-mediated LDLR degradation, resulting in attenuated but not eliminated LDL elevation.
• APOE rs429358 / rs7412 (ε2 allele) — The APOE ε2 isoform reduces LDL-C clearance demand, and ε2 carriers with LDLR mutations sometimes show less severe phenotypes, though this is not consistent across studies.
• rs6511720 (LDLR regulatory intron 1) — This common regulatory variant modestly increases LDLR expression; carriers of both rs6511720 T and rs28942083 A may produce slightly more functional receptor from the non-mutant allele.

These interactions do not eliminate the need for pharmacological treatment but may explain phenotypic variability among heterozygous FH carriers. Compound heterozygosity with a second LDLR pathogenic variant (two different LDLR mutations, one on each chromosome) produces a phenotype approaching that of homozygous FH and requires aggressive management.