rs730882105 — LDLR p.Val524Met

LDLR Val524Met — A Rare Familial Hypercholesterolemia Mutation

The LDL receptor (LDLR) encoded by the LDLR gene is the primary mechanism by which the liver clears low-density lipoprotein (LDL) cholesterol from the bloodstream. Each functional LDLR molecule captures LDL particles at the hepatocyte surface and draws them into the cell via receptor-mediated endocytosis, where cholesterol is released for cellular use. Pathogenic LDLR mutations disrupt this clearance system, allowing LDL cholesterol to accumulate in the blood from birth — the defining feature of familial hypercholesterolemia (FH)¹¹ familial hypercholesterolemia (FH)
autosomal dominant disorder causing severe, lifelong LDL-C elevation and dramatically accelerated atherosclerosis.

rs730882105 is an extremely rare missense variant in LDLR that substitutes methionine for valine at amino acid position 524 (c.1570G>A, p.Val524Met). It has been classified as likely pathogenic by the British Heart Foundation LDLR-LOVD database²² likely pathogenic by the British Heart Foundation LDLR-LOVD database
the LDLR Leiden Open Variation Database maintained by the BHF is the most comprehensive curated registry of LDLR variants with clinical significance assignments, though a second submitter classified it as uncertain significance under stricter ACMG 2015 criteria, and a Merck Research Labs functional study found no significant impairment in vitro. The conflicting evidence reflects a genuine ambiguity in this rare variant: population frequency is too low for robust statistical association, and functional assay results diverge from clinical reports. This YAML entry reflects the intermediate evidence state.

The Mechanism

Val524 sits within the [ligand-binding domain cluster of LDLR | the extracellular ligand-binding domain consists of seven cysteine-rich repeats (LBD1–7) that directly contact apolipoprotein B-100 on LDL particles and apolipoprotein E on VLDL/IDL particles] — specifically in or near repeat 7 (LBD-7), a region required for efficient LDL binding and cellular uptake. Valine-to-methionine substitutions introduce a larger, more polar side chain that can disrupt the local protein conformation, though the magnitude of functional impairment varies by exact position and surrounding structure. The Merck in vitro data suggesting no effect may reflect assay conditions not replicating the full hepatic context of LDL binding and recycling; real-world FH reports in carriers are the stronger signal for a receptor with known genotype-phenotype correlation.

Untreated heterozygous FH (one mutated LDLR copy) typically produces LDL-C of 190–400 mg/dL from birth — levels that accelerate atherosclerotic plaque formation decades earlier than in the general population. Ference et al. 2017³³ Ference et al. 2017
Low-density lipoproteins cause atherosclerotic cardiovascular disease. European Heart Journal established that the cumulative LDL burden from birth (not just current levels) drives atherosclerosis; this is why FH carriers begin accumulating plaques in their teens and 20s and may have their first myocardial infarction before age 50.

The Evidence

rs730882105 is too rare (2 alternate alleles in 1.4 million gnomAD samples) to accumulate direct statistical evidence for this specific variant. Its likely pathogenic classification rests on: (1) location in a functionally critical LDLR domain; (2) clinical reports of FH phenotype in at least one carrier submitted to the LDLR-LOVD; (3) the prior probability that missense variants disrupting LDLR ligand-binding repeats are pathogenic, which is high based on the 3,200+ characterized LDLR variants catalogued by Abifadel & Boileau 2023⁴⁴ Abifadel & Boileau 2023
Genetic and molecular architecture of familial hypercholesterolemia. J Intern Med, where missense variants account for ~60% of all pathogenic LDLR mutations.

The broader FH evidence base is compelling: untreated heFH carries a [substantially elevated risk of CHD | coronary heart disease — up to 13-fold excess risk per the EAS consensus] Defesche et al. 2017⁵⁵ Defesche et al. 2017
Familial hypercholesterolaemia. Nat Rev Dis Primers. The global prevalence of FH is approximately 1:250 (1:80 in founder populations such as French Canadians and Afrikaners) — far higher than previously thought. Most remain undiagnosed. Tokgozoglu & Kayikcioglu 2021⁶⁶ Tokgozoglu & Kayikcioglu 2021
Familial Hypercholesterolemia: Global Burden and Approaches. Curr Cardiol Rep estimated that >85% of FH individuals globally are undetected. With statin therapy achieving ≥50% LDL reduction, the excess cardiovascular risk is substantially attenuated — making early identification and treatment directly life-extending.

Practical Actions

Heterozygous carriers of rs730882105 should have a fasting lipid panel performed to establish baseline LDL-C levels. LDL-C >190 mg/dL in an adult with a likely pathogenic LDLR variant typically meets criteria for high-intensity statin therapy (rosuvastatin 20–40 mg or atorvastatin 40–80 mg). The LDL-C target is <100 mg/dL for those without established cardiovascular disease, and <70 mg/dL for those with prior ASCVD events. If statin therapy alone is insufficient, ezetimibe (adds ~15% LDL reduction) and PCSK9 inhibitors (alirocumab, evolocumab — add ~50% LDL reduction) are guideline-recommended additions. Sturm et al. 2018⁷⁷ Sturm et al. 2018
Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel recommends cascade screening of all first-degree relatives when a pathogenic LDLR variant is identified — each child of a carrier has a 50% chance of inheriting the mutation.

Saturated fat restriction to below 7% of total calories specifically reduces hepatic LDL production and complements statin therapy in FH; this is one of few dietary interventions with FH-specific evidence because it operates through the same LDL-receptor pathway that LDLR mutations impair.

Interactions

LDLR variants interact in severity with PCSK9 gain-of-function variants (rs28942078, rs72658867) and APOB p.Arg3527Gln: carriers of both a pathogenic LDLR variant and a PCSK9 gain-of-function variant have substantially more severe LDL elevation than either alone, as PCSK9 degrades the LDL receptor — compounding the LDLR mutation's reduced receptor availability. Double heterozygotes are estimated to have FH severity approaching homozygous FH. APOE ε4 (rs429358) also modestly elevates LDL-C and is relevant context for cardiovascular risk assessment in carriers.