rs121918390 — APOB APOB R2522X

Nonsense mutation truncating apolipoprotein B at residue 2522, causing familial hypobetalipoproteinemia with characteristically low LDL-C, hepatic steatosis, and potential fat-soluble vitamin insufficiency in heterozygous carriers

See your personal result for APOB

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

APOB R2522X — When Your Liver Makes Half an Apolipoprotein B

Apolipoprotein B (apoB) is the structural backbone of every LDL, VLDL, and chylomicron particle your liver makes. Without a full-length apoB-100, your liver cannot build and secrete normal LDL particles, so your circulating LDL cholesterol stays characteristically and permanently low11 characteristically and permanently low
Heterozygous FHBL carriers almost always have LDL-C below 70 mg/dL regardless of diet, a lifelong trait caused by the variant, not by healthy lifestyle. This sounds like good news — and for cardiovascular health, it mostly is — but the same impaired lipid-export machinery creates two clinically relevant risks: fat accumulation in the liver and impaired transport of fat-soluble vitamins.

The Mechanism

The R2522X variant introduces a premature stop codon at amino acid 2,522 of the 4,536-amino-acid apoB-100 protein (c.7564C>T on the coding strand; G>A on the GRCh38 plus strand). The resulting truncated protein — called apoB-5522 apoB-55
The "55" refers to the fact that the truncated protein is approximately 55% the length of full-length apoB-100 — comprises about 55% of the normal protein length and is secreted at roughly 37–40% of the normal molar rate compared to wild-type apoB-100, consistent with the linear relationship between truncation length and secretion efficiency demonstrated by Parhofer et al.33 demonstrated by Parhofer et al.
Parhofer et al. Positive linear correlation between the length of truncated apolipoprotein B and its secretion rate. J Lipid Res, 1996. The half of the protein that is missing includes domains critical for maximal lipid recruitment into the lipoprotein particle core.

Because apoB is the only structural protein on LDL particles, each cell carries one normal APOB allele and one truncating allele. The liver produces both full-length apoB-100 and the shorter apoB-55, but the truncated version carries less lipid cargo per particle, and fewer lipid-laden particles leave the liver — so hepatocytes accumulate triglycerides that cannot be exported.

The Evidence

The R2522X variant was first identified in the early 1990s in patients with unexplained low cholesterol. The same CGA→TGA change at the CpG dinucleotide hot spot in exon 26 was later independently rediscovered in a second kindred by Gabelli et al.44 Gabelli et al.
Gabelli et al. Diabetes mellitus in a new kindred with familial hypobetalipoproteinemia and an apolipoprotein B truncation (apoB-55). Atherosclerosis, 1998, whose proband had LDL-C of 44 mg/dL and detectable plasma apoB-55 on immunoblotting. Notably, the proband and his father both had type 2 diabetes, yet neither had clinically manifest macrovascular complications — consistent with the cardiovascular-protective effect of lifelong low LDL-C.

The apoB-55 truncation falls in a zone where the protein can still be secreted and detected in plasma (unlike very short truncations below ~apoB-30, which are not detectable in plasma at all). Its secretion efficiency of ~37% of normal means heterozygotes lose roughly a third of their normal VLDL export capacity, explaining the 3-to-5-fold increase in hepatic fat content that characterizes FHBL, as reviewed by Schonfeld55 Schonfeld
Schonfeld G. Familial hypobetalipoproteinemia: a review. J Lipid Res, 2003.

A systematic literature review by Molk et al.66 Molk et al.
Molk et al. Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant. Front Med, 2023 confirms that fatty liver disease occurs even in heterozygous carriers and can present in childhood. About 5–10% of heterozygous FHBL individuals develop more severe nonalcoholic steatohepatitis requiring medical attention.

Practical Actions

For heterozygous carriers the most important immediate step is establishing a baseline: a fasting lipid panel confirms the expected low LDL-C and rules out concurrent dyslipidemia; liver enzymes (AST/ALT) and a hepatic ultrasound screen for steatosis; and serum levels of vitamins A, D, E, and K evaluate fat-soluble vitamin status. Because apoB-containing lipoprotein particles are the primary carriers of fat-soluble vitamins from the gut into circulation, impaired VLDL/chylomicron secretion can subtly reduce vitamin transport even when dietary intake is adequate. Supplementation with water-dispersible or emulsified forms of vitamins D, E, A, and K corrects any measured deficiency efficiently.

Dietary saturated fat restriction is not the goal here (unlike APOE4) — in fact, very low fat diets can worsen fat-soluble vitamin absorption. The aim is identifying and correcting any subclinical deficiency before it causes neurological or ophthalmological consequences.

Cardiovascular risk is paradoxically reduced: lifelong LDL-C below 70 mg/dL confers protection against atherosclerosis, and carriers need not take statins for lipid-lowering purposes. However, the reduced LDL does not protect against the metabolic consequences of obesity or insulin resistance, so maintaining a healthy metabolic profile remains relevant.

Interactions

In the rare case of a compound heterozygote or homozygote for APOB loss-of-function variants, the phenotype resembles abetalipoproteinemia (severe fat malabsorption, acanthocytosis, retinitis pigmentosa, progressive ataxia). Interaction with APOE genotype (rs429358, rs7412) is worth noting conceptually: APOE4 would ordinarily raise LDL cholesterol, but an APOB truncating variant overrides this by limiting the number of LDL particles produced rather than their clearance rate. The net effect in a double carrier would still be low LDL-C, driven by impaired production.

Nutrient Interactions

vitamin A reduced_absorption
vitamin D reduced_absorption
vitamin E reduced_absorption
vitamin K reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

Normal APOB — standard apolipoprotein B production

You do not carry the APOB R2522X truncation. Your apolipoprotein B gene produces full-length apoB-100, enabling normal VLDL and LDL particle assembly and secretion. About 99.995% of people share this genotype. Your LDL-C and fat-soluble vitamin transport are not affected by this variant.

AA Homozygous (Very Rare) Absent

Both APOB copies truncated — severe lipoprotein deficiency

Homozygous or compound heterozygous APOB loss-of-function causes biallelic familial hypobetalipoproteinemia (FHBL2), functionally similar to abetalipoproteinemia caused by MTP mutations. Total plasma cholesterol is typically below 40 mg/dL, LDL is virtually undetectable, and fat-soluble vitamins (A, D, E, K) become severely depleted without high-dose supplementation. The clinical consequences of untreated severe deficiency include retinitis pigmentosa (irreversible), spinocerebellar ataxia, peripheral neuropathy, and coagulopathy from vitamin K deficiency. Early diagnosis and supplementation prevent most complications.

Note: If this result comes from a consumer genotyping chip, technical error (non-reference homozygous call at an ultra-rare site) should be excluded by confirmatory sequencing before acting on this result.

AG Heterozygous Carrier Carrier

One APOB R2522X copy — low LDL-C, monitor liver and fat-soluble vitamins

The apoB-55 truncation removes 45% of the protein, including the carboxyl-terminal lipid-binding domains. The truncated protein is secreted at roughly 37% of the molar rate of wild-type apoB-100, consistent with the linear truncation-length/secretion relationship documented by Parhofer et al. (PMID 8732784). This means your liver exports fewer lipid-carrying particles per unit time, resulting in intrahepatic triglyceride accumulation and reduced circulating LDL.

Fat-soluble vitamin (A, D, E, K) transport depends on their incorporation into chylomicrons (made in the gut using apoB-48, which is unaffected by this variant) and their redistribution via VLDL/LDL. Chylomicron production remains intact for dietary fat absorption, so severe malabsorption is not expected in heterozygotes. However, subclinical reductions in vitamins D and E have been documented in FHBL series, and clinical assessment is warranted.