rs121918383 — APOB APOB Arg1333Ter

APOB Arg1333Ter — A Rare Truncating Variant That Dramatically Lowers LDL

Apolipoprotein B-100 (apoB-100) is the structural backbone of every LDL particle¹¹ LDL particle
Low-density lipoprotein: the primary cholesterol-carrying particle in blood; high levels are a major cardiovascular risk factor. Without apoB-100, the liver cannot package and export VLDL — and without VLDL, there is no LDL. The rs121918383 A allele introduces a premature stop codon at position 1333 of the protein, producing a severely truncated apoB fragment (apoB-30) that is too short to assemble into lipoprotein particles and is degraded before it reaches the bloodstream. The result is a dramatic reduction in circulating LDL cholesterol — a condition called familial hypobetalipoproteinemia (FHBL)²² familial hypobetalipoproteinemia (FHBL)
FHBL: an autosomal codominant disorder characterized by plasma LDL and apoB levels below the 5th percentile for age and sex.

The Mechanism

APOB resides on chromosome 2 and is transcribed from the minus strand. The rs121918383 A allele on the plus (forward) strand corresponds to a C→T change on the coding strand transcript (NM_000384.3:c.3997C>T), converting the codon for arginine-1333 to a stop codon (UAA). The resulting apoB-30 protein — only 30% of the full 4,536-amino-acid sequence — lacks the lipid-binding domains required for VLDL assembly and is rapidly degraded intracellularly. Truncated apoB fragments shorter than apoB-30³³ Truncated apoB fragments shorter than apoB-30
Yue et al. Novel mutations of APOB cause ApoB truncations undetectable in plasma and familial hypobetalipoproteinemia. Hum Mutat, 2002 are invariably undetectable in plasma, which means heterozygous carriers present with a single functional APOB allele producing roughly 50% of the normal apoB-100 output — and correspondingly very low LDL cholesterol.

The Evidence

This is an autosomal codominant disorder: one copy reduces LDL substantially; two copies cause severe disease. Heterozygous carriers typically have plasma LDL-C and apoB below the 5th centile for age and sex, with total cholesterol often 30–50% below population norms. A 2020 meta-analysis of 12 case-control studies⁴⁴ A 2020 meta-analysis of 12 case-control studies
Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol, 2020 covering 57,973 individuals found that APOB protein-truncating variants confer a 72% reduction in coronary heart disease risk (OR 0.28, 95% CI 0.12–0.64) — making this one of the strongest single-gene cardiovascular protective effects in the human genome.

Heterozygous carriers are usually asymptomatic. A minority develop hepatic steatosis⁵⁵ hepatic steatosis
Fatty liver: impaired hepatic lipid export due to reduced VLDL assembly causes triglycerides to accumulate in liver cells from impaired hepatic lipid export; this rarely progresses to steatohepatitis or cirrhosis. Burnett, Hooper, and Hegele's GeneReviews chapter⁶⁶ Burnett, Hooper, and Hegele's GeneReviews chapter
Burnett JR et al. APOB-Related Familial Hypobetalipoproteinemia. GeneReviews, 2021 estimates 5–10% of heterozygotes develop clinically significant liver dysfunction.

The extremely rare homozygous state (both APOB alleles non-functional) mimics abetalipoproteinemia⁷⁷ abetalipoproteinemia
A severe disorder with complete absence of apoB-containing lipoproteins, causing fat malabsorption and fat-soluble vitamin deficiencies from birth and requires intensive clinical management from infancy.

Practical Actions

For heterozygous carriers, the primary clinical implication is cardiovascular protection from very low LDL — but liver surveillance is warranted because of the hepatic steatosis risk. Periodic liver function tests and liver imaging can catch early steatohepatitis before it progresses. A 2006 study⁸⁸ 2006 study
Clarke et al. Assessment of tocopherol metabolism and oxidative stress in familial hypobetalipoproteinemia. Clin Chem, 2006 found that heterozygous FHBL patients have lower absolute vitamin E levels, but when corrected for the low lipid-carrier concentration, tissue tocopherol status is normal — routine vitamin E supplementation is NOT indicated for heterozygotes. Dietary fat restriction is not necessary for heterozygotes. Dietary choices that support liver health (limiting excess fructose, alcohol, and ultra-processed foods) are especially relevant given the hepatic steatosis risk.

Biallelic carriers (homozygotes) require specialist management: high-dose fat-soluble vitamins (vitamins A, D, E, K), dietary fat restriction (<30% of calories), and regular neurological, ophthalmological, and hepatic surveillance. These individuals should be under care of a metabolic disease specialist.

Interactions

rs121918383 shares the same disease mechanism with other APOB truncating variants including rs121918384 (Val1856fs frameshift). Carriers of truncating mutations in APOB in combination with APOE genotype (rs429358/rs7412) show variable LDL levels — APOE ε4 carriers with FHBL may have higher LDL than expected from the truncating mutation alone, while ε2 carriers may have even lower LDL.