Hypercholesterolemia, familial, 1: genes and variants

Genes linked to Hypercholesterolemia, familial, 1

• 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.

  558 disease-causing and 584 uncertain variants in LDLR are linked to Hypercholesterolemia, familial, 1.

• 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.

  8 disease-causing and 19 uncertain variants in PCSK9 are linked to Hypercholesterolemia, familial, 1.

• 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 42 uncertain variants in APOB are linked to Hypercholesterolemia, familial, 1.

• GHR: Growth hormone receptor

  Its activation by growth hormone triggers JAK2-STAT signaling that promotes IGF-1 production, linear growth, and metabolic effects. Biallelic or dominant-negative loss-of-function variants can cause growth-hormone insensitivity, while activating alterations are rare.

  0 disease-causing and 6 uncertain variants in GHR are linked to Hypercholesterolemia, familial, 1.

Weakly linked (only a few uncertain records): ABCA1 and G6PD.

Where Hypercholesterolemia, familial, 1 variants cluster

• LDLR Binding to Getah virus E1-E2 spike glycoproteins (positions 146–233): 98 of 558 disease-causing changes, 1.7× more than its size predicts.
• LDLR LDL-receptor class A 3 (positions 107–145): 54 of 558 disease-causing changes, 2.1× more than its size predicts.

Known disease-causing variants in Hypercholesterolemia, familial, 1

Showing 60 of 568.

Which prediction tools work for Hypercholesterolemia, familial, 1

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

• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 98 out of 100
• AlphaMissense: 97 out of 100
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 87 out of 100
• SIFT: 85 out of 100
• phyloP: 78 out of 100
• ESM1b (LLR): 48 out of 100

Same protein, different disease

• Familial hypercholesterolemia is also caused by LDLR variants; they fall in the same places as the Hypercholesterolemia, familial, 1 variants (296 disease-causing).
• Dyslipidemia is also caused by LDLR variants; they fall in the same places as the Hypercholesterolemia, familial, 1 variants (32 disease-causing).
• Homozygous familial hypercholesterolemia is also caused by LDLR variants; they fall in the same places as the Hypercholesterolemia, familial, 1 variants (26 disease-causing).
• Familial hypobetalipoproteinemia 1 is also caused by APOB variants; they fall mostly in different places as the Hypercholesterolemia, familial, 1 variants (7 disease-causing).

Diseases related to Hypercholesterolemia, familial, 1

• Familial hypercholesterolemia, also linked to APOB, LDLR and PCSK9
• Homozygous 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
• Monogenic short statue, also linked to GHR
• Laron-type isolated somatotropin defect, also linked to GHR
• Hypercholesterolemia, autosomal dominant, type B, also linked to APOB
• Chronic kidney disease, also linked to GHR
• Short stature due to partial GHR deficiency, also linked to GHR

Frequently asked questions

Which genes are linked to Hypercholesterolemia, familial, 1?

In CATVariant, Hypercholesterolemia, familial, 1 is linked to 4 analyzed proteins: LDLR (Low-density lipoprotein receptor), PCSK9 (Proprotein convertase subtilisin/kexin type 9), APOB (Apolipoprotein B-100) and GHR (Growth hormone receptor).

How many genetic variants are linked to Hypercholesterolemia, familial, 1?

1,326 variants: 568 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 653 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hypercholesterolemia, familial, 1 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 Hypercholesterolemia, familial, 1?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 433 disease-causing and 20 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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