Von Hippel-Lindau syndrome: genes and variants

Genes linked to Von Hippel-Lindau syndrome

• VHL: von Hippel-Lindau disease tumor suppressor

  It targets hydroxylated HIF-alpha proteins for ubiquitin-mediated degradation when oxygen is sufficient, keeping hypoxia-response programs suppressed. Loss of function stabilizes HIF signaling and causes von Hippel-Lindau tumor-predisposition syndrome while also driving most clear-cell renal carcinomas.

  147 disease-causing and 456 uncertain variants in VHL are linked to Von Hippel-Lindau syndrome.

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

Where Von Hippel-Lindau syndrome variants cluster

• VHL Interaction with Elongin BC complex (positions 157–166): 17 of 147 disease-causing changes, 2.5× more than its size predicts.

Known disease-causing variants in Von Hippel-Lindau syndrome

Showing 60 of 147.

Uncertain variants in Von Hippel-Lindau syndrome that look disease-causing

Which prediction tools work for Von Hippel-Lindau syndrome

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

• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 91 out of 100
• MetaLR: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 74 out of 100
• SIFT: 74 out of 100

Diseases related to Von Hippel-Lindau syndrome

• Chuvash polycythemia, also linked to VHL
• Pheochromocytoma, also linked to VHL
• Inherited phaeochromocytoma and paraganglioma excluding NF1, also linked to VHL
• Nonpapillary renal cell carcinoma, also linked to VHL
• Renal cell carcinoma, also linked to VHL

Frequently asked questions

Which genes are linked to Von Hippel-Lindau syndrome?

In CATVariant, Von Hippel-Lindau syndrome is linked to 1 analyzed protein: VHL (von Hippel-Lindau disease tumor suppressor).

How many genetic variants are linked to Von Hippel-Lindau syndrome?

612 variants: 147 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 457 are of uncertain significance or have conflicting reports.

Which uncertain variants in Von Hippel-Lindau syndrome look disease-causing?

10 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example VHL V130I, VHL R64H, VHL I151V, VHL P154R and VHL D197A. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Von Hippel-Lindau syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 32 disease-causing and 27 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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