Homozygous familial hypercholesterolemia: genes and variants

Genes linked to Homozygous 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.

  26 disease-causing and 1 uncertain variants in LDLR are linked to Homozygous 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 1 uncertain variants in APOB are linked to Homozygous 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 0 uncertain variants in PCSK9 are linked to Homozygous familial hypercholesterolemia.

Where Homozygous familial hypercholesterolemia variants cluster

• LDLR LDL-receptor class A 5 (positions 195–233): 5 of 26 disease-causing changes, 4.2× more than its size predicts.
• LDLR LDL-receptor class B 4 (positions 529–572): 4 of 26 disease-causing changes, 3.0× more than its size predicts.
• LDLR LDL-receptor class A 3 (positions 107–145): 3 of 26 disease-causing changes, 2.5× more than its size predicts.

Known disease-causing variants in Homozygous familial hypercholesterolemia

Which prediction tools work for Homozygous familial hypercholesterolemia

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

• MutPred2: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 98 out of 100
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 98 out of 100
• CADD: 93 out of 100
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 88 out of 100
• phyloP: 87 out of 100

Same protein, different disease

• Hypercholesterolemia, familial, 1 is also caused by LDLR variants; they fall mostly in different places as the Homozygous familial hypercholesterolemia variants (558 disease-causing).
• Familial hypercholesterolemia is also caused by LDLR variants; they fall mostly in different places as the Homozygous familial hypercholesterolemia variants (296 disease-causing).
• Dyslipidemia is also caused by LDLR variants; they fall mostly in different places as the Homozygous familial hypercholesterolemia variants (32 disease-causing).
• Familial hypobetalipoproteinemia 1 is also caused by APOB variants; they fall mostly in different places as the Homozygous familial hypercholesterolemia variants (7 disease-causing).
• Hypercholesterolemia, familial, 1 is also caused by PCSK9 variants; they fall mostly in different places as the Homozygous familial hypercholesterolemia variants (8 disease-causing).

Diseases related to Homozygous familial hypercholesterolemia

• Hypercholesterolemia, familial, 1, also linked to APOB, LDLR and PCSK9
• Familial hypercholesterolemia, also linked to APOB, LDLR and PCSK9
• Myocardial infarction, also linked to APOB, LDLR and PCSK9
• Dyslipidemia, also linked to LDLR
• Familial hypobetalipoproteinemia 1, also linked to APOB
• Hypercholesterolemia, autosomal dominant, type B, also linked to APOB

Frequently asked questions

Which genes are linked to Homozygous familial hypercholesterolemia?

In CATVariant, Homozygous familial hypercholesterolemia is linked to 3 analyzed proteins: LDLR (Low-density lipoprotein receptor), APOB (Apolipoprotein B-100) and PCSK9 (Proprotein convertase subtilisin/kexin type 9).

How many genetic variants are linked to Homozygous familial hypercholesterolemia?

31 variants: 29 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2 are of uncertain significance or have conflicting reports.

Which uncertain variants in Homozygous 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 Homozygous 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 14 disease-causing and 54 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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