rs12713559 — APOB APOB R3558C

APOB R3558C — A Rare LDL Receptor-Binding Variant of Uncertain Significance

Apolipoprotein B-100 (ApoB) is the structural backbone of LDL particles — every LDL particle carries exactly one ApoB-100 protein, and it is this protein that docks with the LDL receptor on liver cells to clear LDL from the bloodstream. The rs12713559 variant causes a cysteine to replace an arginine at position 3558 of the ApoB protein, in the segment responsible for LDL receptor binding. This disrupts LDL clearance, but to a degree that varies considerably between individuals.

The Mechanism

The p.Arg3558Cys substitution (historically called R3531C in earlier numbering systems) sits within the proposed LDL receptor-binding domain of ApoB. Arginine at position 3558 contributes to the cluster of positively charged residues that interact electrostatically with the LDL receptor. Replacing it with cysteine introduces a sulfhydryl group and removes a positive charge, impairing the ApoB-LDL receptor interaction.

Functional assays¹¹ Functional assays
Pullinger CR et al. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest, 1995 show that LDL particles from R3558C heterozygotes bind to the LDL receptor at roughly 50-63% of normal affinity. In competitive binding assays using U937 cells, the defective particles were 74% as effective as normal LDL and accumulated preferentially compared to the wild-type allotype — meaning mutant LDL persists longer in circulation.

The Evidence

The discovery report²² discovery report
Pullinger CR et al. J Clin Invest, 1995 identified the variant in two unrelated families; all eight carriers showed elevated cholesterol (mean 240 mg/dL) versus unaffected relatives (185 mg/dL). The gene sits on the minus strand; the coding-strand change is C>T at position 10672 of NM_000384.3.

A larger kindred study³³ larger kindred study
Ouguerram K et al. The apolipoprotein B R3531C mutation. Characteristics of 24 subjects from 9 kindreds. J Lipid Res, 1999 of 24 carriers from 9 kindreds confirmed the binding deficit but found highly variable LDL cholesterol expression, modulated by environmental and other genetic factors.

Crucially, a large population-based study⁴⁴ population-based study
Tybjaerg-Hansen A et al. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. NEJM, 1998 of 9,255 Danish individuals found R3558C heterozygotes (0.08% prevalence) did not have higher-than-normal plasma cholesterol levels, and the association with ischemic heart disease was not significant (OR 1.4, 95% CI 0.2-11, p=0.54). This contrasts sharply with the well-characterized R3500Q variant (rs5742904), which is 10-fold more prevalent and is a well-established cause of familial defective apolipoprotein B (FDB) with OR 7.0 for ischemic heart disease.

A family-based segregation study⁵⁵ family-based segregation study
Rabes JP et al. R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia. Atherosclerosis, 2000 found that 6 of 10 R3558C carriers had normal cholesterol, with the mean cholesterol not significantly different between carriers and non-carriers. A co-segregating LDLR mutation was the primary driver of hypercholesterolemia in that family, with R3558C potentially acting as a modifier.

ClinVar now records 14 of 18 submissions as uncertain significance (last updated February 2026). The 1995 OMIM pathogenic entry and one Italian laboratory's "likely pathogenic" call are flagged as not meeting current evidence criteria.

Practical Actions

Because the clinical significance of this variant remains genuinely uncertain, the most appropriate response is cardiovascular risk monitoring through regular lipid panels, not preemptive treatment. Many carriers have normal cholesterol. If LDL is elevated, standard FH-adjacent management applies: dietary saturated fat restriction and statin therapy if needed. The variant does not affect statin mechanism — statins upregulate the LDL receptor, so even with reduced ApoB-LDL receptor affinity, statin response should be intact.

If you are heterozygous for this variant and have elevated LDL cholesterol, genetic testing for LDLR mutations is warranted, as co-occurring LDLR mutations may be driving the lipid phenotype.

Interactions

The clinically important interaction is between rs12713559 and LDLR mutations (not catalogued in this database). Rabes et al. (2000) found that R3558C alone did not cause hypercholesterolemia but may amplify the effect of a concurrent LDLR defect. The related and far more common APOB R3500Q variant (rs5742904) is the canonical cause of familial defective apolipoprotein B; if you also carry APOE E4 (rs429358), independent cardiovascular risk factors stack.