Familial hypercholesterolemia: genes and variants

Genes linked to Familial hypercholesterolemia

• LDLR: Low-density lipoprotein receptor

  It removes ApoB-containing LDL particles from the circulation through receptor-mediated endocytosis, especially in hepatocytes. Loss-of-function variants are the most common cause of familial hypercholesterolemia and lead to lifelong LDL elevation and premature atherosclerotic disease.

  296 disease-causing and 464 uncertain variants in LDLR are linked to Familial hypercholesterolemia.

• APOE: Apolipoprotein E

  It redistributes cholesterol and other lipids between tissues by directing remnant lipoproteins to LDL-receptor-family members. The common epsilon4 isoform strongly increases late-onset Alzheimer disease risk and also influences plasma lipids and cardiovascular risk.

  3 disease-causing and 14 uncertain variants in APOE are linked to Familial hypercholesterolemia.

• APOB: Apolipoprotein B-100

  It provides the structural backbone for triglyceride-rich lipoproteins and LDL, while ApoB-100 also mediates LDL-receptor binding and clearance. Pathogenic variants can cause familial hypobetalipoproteinemia or defective ApoB-related hypercholesterolemia depending on their effect on particle assembly and receptor binding.

  2 disease-causing and 69 uncertain variants in APOB are linked to Familial hypercholesterolemia.

• PCSK9: Proprotein convertase subtilisin/kexin type 9

  By binding hepatic LDL receptors and promoting their lysosomal degradation, it reduces receptor recycling and raises circulating LDL cholesterol. Gain-of-function variants cause autosomal dominant hypercholesterolemia, whereas loss-of-function variants lower LDL cholesterol and cardiovascular risk.

  1 disease-causing and 400 uncertain variants in PCSK9 are linked to Familial hypercholesterolemia.

• ANGPTL3: Angiopoietin-related protein 3

  It restrains lipoprotein and endothelial lipases, thereby increasing circulating triglyceride and HDL-cholesterol levels. Loss-of-function variants produce familial combined hypolipidemia and are associated with lower atherosclerotic cardiovascular risk, making the pathway a therapeutic target.

  0 disease-causing and 0 uncertain variants in ANGPTL3 are linked to Familial hypercholesterolemia.

• HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase

  It controls the rate-limiting step of the mevalonate pathway and therefore strongly regulates endogenous cholesterol production. Statins lower LDL cholesterol by inhibiting this activity, causing the liver to increase LDL-receptor-mediated clearance from blood.

  0 disease-causing and 0 uncertain variants in HMGCR are linked to Familial hypercholesterolemia.

Weakly linked (only a few uncertain records): ABCA1.

Where Familial hypercholesterolemia variants cluster

• LDLR Binding to Getah virus E1-E2 spike glycoproteins (positions 146–233): 63 of 296 disease-causing changes, 2.1× more than its size predicts.
• LDLR LDL-receptor class A 3 (positions 107–145): 32 of 296 disease-causing changes, 2.4× more than its size predicts.
• LDLR EGF-like 2 (positions 354–393): 26 of 296 disease-causing changes, 1.9× more than its size predicts.
• LDLR LDL-receptor class B 4 (positions 529–572): 24 of 296 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Familial hypercholesterolemia

Showing 60 of 302.

Which prediction tools work for Familial hypercholesterolemia

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• AlphaMissense: 98 out of 100
• EVE: 98 out of 100
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 86 out of 100
• phyloP: 80 out of 100

Same protein, different disease

• Hypercholesterolemia, familial, 1 is also caused by LDLR variants; they fall in the same places as the Familial hypercholesterolemia variants (558 disease-causing).
• Dyslipidemia is also caused by LDLR variants; they fall in the same places as the Familial hypercholesterolemia variants (32 disease-causing).
• Homozygous familial hypercholesterolemia is also caused by LDLR variants; they fall in the same places as the Familial hypercholesterolemia variants (26 disease-causing).
• Familial type 3 hyperlipoproteinemia is also caused by APOE variants; they fall mostly in different places as the Familial hypercholesterolemia variants (10 disease-causing).
• Familial hypobetalipoproteinemia 1 is also caused by APOB variants; they fall mostly in different places as the Familial hypercholesterolemia variants (7 disease-causing).
• Hypercholesterolemia, familial, 1 is also caused by PCSK9 variants; they fall mostly in different places as the Familial hypercholesterolemia variants (8 disease-causing).

Diseases related to Familial hypercholesterolemia

• Myocardial infarction, also linked to APOB, APOE, HMGCR, LDLR and 1 more
• Hypercholesterolemia, familial, 1, also linked to APOB, LDLR and PCSK9
• Homozygous familial hypercholesterolemia, also linked to APOB, LDLR and PCSK9
• Alzheimer disease, also linked to APOE and HMGCR
• Type 2 diabetes mellitus, also linked to APOE and HMGCR
• Hyperlipoproteinemia, also linked to APOE and HMGCR
• Familial hypobetalipoproteinemia 1, also linked to ANGPTL3 and APOB
• Age related macular degeneration 9, also linked to APOE
• Dyslipidemia, also linked to LDLR
• Familial type 3 hyperlipoproteinemia, also linked to APOE
• Diabetes mellitus, also linked to APOE
• Lewy body dementia, also linked to APOE

Frequently asked questions

Which genes are linked to Familial hypercholesterolemia?

In CATVariant, Familial hypercholesterolemia is linked to 6 analyzed proteins: LDLR (Low-density lipoprotein receptor), APOE (Apolipoprotein E), APOB (Apolipoprotein B-100), PCSK9 (Proprotein convertase subtilisin/kexin type 9), ANGPTL3 (Angiopoietin-related protein 3) and HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase).

How many genetic variants are linked to Familial hypercholesterolemia?

1,282 variants: 302 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 948 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial hypercholesterolemia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Familial hypercholesterolemia?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 226 disease-causing and 56 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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