rs606231236 — APOB

Pathogenic APOB splice acceptor variant causing familial hypobetalipoproteinemia — heterozygous carriers have ~50% lower LDL-C and apoB, conferring cardiovascular protection but requiring liver and fat-soluble vitamin monitoring

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APOB Splice Acceptor Variant — A Rare Cause of Familial Hypobetalipoproteinemia

Most people fear high LDL cholesterol, but some individuals carry a variant that drives LDL in the opposite direction — dramatically lower than normal. This APOB splice acceptor variant (c.905-1_905dup) was first identified in a consanguineous French Canadian11 French Canadian
Consistent with a known founder-effect population where rare variants are enriched due to a restricted founding population family and is one of the rarest documented pathogenic APOB mutations. It belongs to a class of APOB protein-truncating variants associated with familial hypobetalipoproteinemia (FHBL) — a condition of chronically very low LDL and apolipoprotein B levels.

The Mechanism

The APOB gene (chromosome 2) encodes apolipoprotein B-10022 apolipoprotein B-100
the scaffolding protein of LDL particles that is recognized by LDL receptors in the liver and peripheral tissues for particle clearance, the structural protein of very-low-density lipoprotein (VLDL) and LDL particles. The rs606231236 variant is a 2-base-pair duplication (CC→CCCC) at the acceptor splice site preceding exon 9 (NM_000384.3:c.905-1_905dup). This disrupts the consensus AG dinucleotide that the spliceosome recognizes to cut incoming intron 8 and join it to exon 9. The result is aberrant mRNA splicing, a frameshift, and production of a severely truncated apoB protein estimated at approximately 7% of normal apoB-100 length33 7% of normal apoB-100 length
ApoB-100 is 4,563 amino acids; a ~7% truncation produces approximately 319 amino acids — far too short to assemble an LDL particle. This truncated protein is not secreted into plasma as a lipoprotein constituent. Heterozygous carriers produce roughly half the normal quantity of functional apoB-100, cutting LDL particle assembly and secretion by approximately half.

The Evidence

The variant was characterized in a French Canadian family where the proband and two siblings were homozygous — carrying two copies of the insertion — and had undetectable plasma apoB and extremely low cholesterol levels44 undetectable plasma apoB and extremely low cholesterol levels
Total cholesterol <20 mg/dL, essentially undetectable LDL-C in homozygotes. Their obligate-heterozygote parents had plasma apoB and LDL-C at approximately 50% of normal, consistent with the codominant pattern expected for APOB truncating variants. The pathogenic classification in ClinVar (RCV000032601) is based solely on this family report, reflecting the rarity of the variant.

At the population level, rare APOB protein-truncating variants as a class have been studied in large cohorts. Peloso et al. 201955 Peloso et al. 2019
Peloso GM et al. Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease. Circ Genom Precis Med 2019 analyzed 57,973 individuals across 12 case-control studies and found APOB PTV carriers had a 43 mg/dL lower LDL-C, a 30% reduction in triglycerides, and an impressive 72% lower risk of coronary heart disease (OR 0.28; 95% CI 0.12–0.64). This cardiovascular protection reflects the established LDL-lowering hypothesis: lifelong low LDL-C confers sustained protection against atherosclerosis.

The flip side of APOB loss of function is hepatic fat accumulation. Because apoB-containing lipoproteins are the primary vehicles for exporting triglycerides from the liver, reducing apoB secretion causes intrahepatic lipid retention — the same mechanism behind non-alcoholic fatty liver disease. Burnett et al. 200966 Burnett et al. 2009
Burnett JR et al. Functional analysis of two novel splice site mutations of APOB gene in familial hypobetalipoproteinemia. J Lipid Res 2009 documented hepatomegaly, elevated liver enzymes, and macrovesicular steatosis in heterozygous APOB splice variant carriers. A 2024 review found that 5–10% of heterozygous APOB-FHBL carriers develop significant nonalcoholic steatohepatitis77 5–10% of heterozygous APOB-FHBL carriers develop significant nonalcoholic steatohepatitis
NASH requiring medical attention, and rarely progress to cirrhosis. Monitoring is warranted.

Practical Actions

Heterozygous carriers of this variant have markedly lower LDL-C — a feature that is cardioprotective and requires no treatment to lower lipids further. The key clinical concerns are the liver and fat-soluble vitamins. Because apoB-mediated lipoprotein export is impaired, fat-soluble vitamins (A, D, E, K) that travel in chylomicrons and VLDL particles may accumulate incompletely in plasma and tissues. Monitoring fat-soluble vitamin levels and liver function annually is the standard of care for heterozygotes. No specific dietary fat restriction is required for heterozygotes; that intervention is reserved for biallelic (homozygous) cases.

Interactions

Homozygous APOB-FHBL (carrying two copies of any APOB loss-of-function variant) is a distinct and severe pediatric syndrome with near-absent apoB, severe fat malabsorption, and progressive neurological and retinal degeneration. In biallelic cases, aggressive fat-soluble vitamin supplementation and a strict low-fat diet (<30% of calories) are required. The combination of this rs606231236 insertion with any other APOB loss-of-function variant in the same individual would produce a clinical picture resembling biallelic FHBL and warrants specialist consultation. Liver steatosis driven by APOB-FHBL may be compounded by metabolic variants affecting lipid storage, such as PNPLA3 rs738409 (I148M), which increases hepatic fat accumulation through a separate mechanism.

Nutrient Interactions

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

Genotype Interpretations

What each possible genotype means for this variant.

DD Non-carrier Normal

Normal APOB function — standard lipid metabolism

You carry two normal copies of the APOB splice acceptor site. Your liver produces full-length apolipoprotein B-100, which assembles VLDL and LDL particles at normal rates. This is the most common genotype — carried by the vast majority of people worldwide. Your LDL cholesterol and apoB levels reflect your lifestyle, diet, and other genetic factors rather than this variant.

DI Carrier Carrier

One disrupted APOB splice site — ~50% lower LDL-C with liver monitoring needed

The reduced apoB secretion means fewer VLDL particles are exported from the liver, which can cause triglycerides and fat-soluble vitamins to accumulate intracellularly rather than circulating in plasma. Liver enzymes (ALT, AST) should be monitored annually — elevated transaminases in a carrier warrant hepatic ultrasound to assess for steatosis. Despite the low LDL-C, standard cardiovascular prevention guidelines (treating high LDL) do not apply in reverse: there is no evidence that artificially raising LDL in FHBL carriers is beneficial, and their cardiovascular risk is already substantially reduced.

II Homozygous Homozygous

Two disrupted APOB alleles — severe familial hypobetalipoproteinemia requiring specialist care

Without apoB-mediated lipoprotein export, dietary fat and fat-soluble vitamins cannot be efficiently absorbed from the gut or transported from the liver. The neurological and retinal complications — ataxia, loss of reflexes, pigmentary retinopathy, night blindness — are driven by severe, chronic vitamin E deficiency. These complications are preventable with early aggressive supplementation. Hepatomegaly and fatty liver develop because triglycerides accumulate intracellularly without an export vehicle. Strict long-chain fat restriction (often <30% of total calories, with medium-chain triglycerides as an alternative fat source) substantially reduces fat malabsorption and hepatic fat loading.