rs730882105 — LDLR p.Val524Met

Rare LDLR missense variant (c.1570G>A, p.Val524Met) associated with familial hypercholesterolemia; classified as likely pathogenic by the British Heart Foundation LDLR-LOVD registry

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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.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

Common sequence — no LDLR Val524Met variant

The LDLR Val524Met variant is an ultra-rare, likely pathogenic mutation in the LDL receptor gene. Its absence carries no inference about LDL-C levels or FH risk. LDL receptor function in your cells at this codon is intact. Any LDL-C elevation you may have is attributable to other causes — common polygenic variants, APOE isoform, diet, or other conditions. The LDLR gene has over 3,200 documented pathogenic variants; a negative result for one ultra-rare variant is not a negative result for FH overall. Cascade genetic testing for FH in your family should be directed by a lipid specialist or clinical geneticist using comprehensive LDLR/APOB/PCSK9 panel testing, not by single-SNP results.

AG Heterozygous FH Carrier High Risk

One copy of LDLR Val524Met — likely pathogenic for heterozygous familial hypercholesterolemia

Heterozygous FH (one functional and one impaired LDLR allele) reduces LDL receptor clearance capacity by roughly 50%, causing LDL-C to accumulate throughout life. The excess LDL exposure begins at birth, and by young adulthood FH heterozygotes carry atherosclerotic plaque burdens that take decades longer to accumulate in the general population. Without treatment, men with heFH face an approximately 50% risk of a coronary event by age 50; women by age 60.

Note on this specific variant: the clinical evidence for Val524Met's pathogenicity is moderate rather than established. The BHF classification is "likely pathogenic" (not confirmed pathogenic), a second submitter called it uncertain significance, and an in vitro functional study (Merck, 2015) found no significant LDL receptor impairment. These conflicting signals mean clinical interpretation should weigh your measured LDL-C level alongside the genetic result. If your LDL-C is consistently above 190 mg/dL with no other clear cause, the likely pathogenic classification is the most informative interpretation. If your LDL-C is normal, discuss the uncertain significance interpretation with a lipid specialist — it may reflect an attenuated or context-dependent effect.

Cascade screening: each of your first-degree relatives has a 50% chance of carrying this variant. If you have children, LDL-C screening is recommended from age 2–10; if a child's LDL-C is consistently elevated, statin therapy is typically started around age 8–10.

AA Homozygous FH High Risk

Two copies of LDLR Val524Met — consistent with homozygous or compound heterozygous familial hypercholesterolemia

True homozygous FH (hoFH) from identical pathogenic LDLR variants on both alleles is rare even in the most common FH variants (overall prevalence 1:160,000–400,000). For a variant with allele frequency ~0.0000017 in Europeans, the Hardy-Weinberg probability of AA genotype is approximately 3 × 10⁻¹² — essentially zero in any unrelated individual. An AA genotype call at rs730882105 therefore almost certainly represents a sequencing artifact, a hemizygous deletion of the normal allele, or a phasing/mapping error, and should be interpreted with extreme caution.

If this result is genuine, immediate referral to a lipid specialist is urgent. Untreated hoFH causes LDL-C >500 mg/dL, visible tendon and skin xanthomas in childhood, aortic stenosis, and myocardial infarction in the second or third decade of life. LDL apheresis (extracorporeal LDL removal every 1–2 weeks), lomitapide (MTP inhibitor), and gene therapy (early-phase) are the primary interventions for hoFH beyond maximally intensive statin + ezetimibe + PCSK9 inhibitor therapy.

Sanger sequencing or long-read WGS should confirm this call before any clinical action is taken.