Von Hippel-Lindau Disease

von Hippel-Lindau (VHL) disease is a neurocutaneous disorder and hereditary cancer syndrome. VHL gene testing may guide screening and early detection measures, which can lead to improved outcomes.


von Hippel-Lindau (VHL) disease is a neurocutaneous disorder and hereditary cancer syndrome. VHL gene testing may guide screening and early detection measures, which can lead to improved outcomes.

VHL disease is an inherited condition characterized by hemangioblastomas, renal tumors, pheochromocytomas (PCCs), retinal angiomas, pancreatic cysts, and neuroendocrine tumors. VHL disease affects about 1 in every 36,000 individuals.1 Genetic testing can be important for symptomatic individuals to confirm a diagnosis, as well as for at-risk asymptomatic individuals who might benefit from early surveillance and intervention.

Disease Name 
von Hipple-Lindau (VHL) disease
Disease Information 

VHL disease is an autosomal dominant disorder caused by mutations in the VHL tumor suppressor gene.1,2 It is involved in multiple cellular processes, such as tumor suppression, oxygen-related gene expression, and protein assembly.3 About 80% of affected individuals have a familial VHL mutation, while about 20% have a de novo mutation. The diagnosis of VHL disease is typically made based on clinical features.

A clinical diagnosis of VHL disease is reached when an individual with no family history of VHL disease presents with two or more of the following4:

  1. >2 hemangioblastomas of the retina, spine, or brain OR a single hemangioblastoma in association with a visceral manifestation (e.g. multiple kidney or pancreatic cysts)
  2. Renal cell carcinoma
  3. Adrenal or extra-adrenal pheochromocytomas
  4. Endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreas

An individual with a positive family history of VHL disease meets clinical criteria when presenting with one or more of the following4:

  1. Retinal angioma
  2. Spinal or cerebellar hemangioblastoma
  3. Adrenal or extra-adrenal pheochromocytomas
  4. Renal cell carcinoma
  5. Multiple renal and pancreatic cysts

VHL disease can be classified as type 1 (without pheochromocytoma), type 2A (with pheochromocytoma), and type 2B (with pheochromocytoma and renal cell carcinoma).5 Type 2C refers to individuals with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. Those with type 1 VHL disease are typically found to have deletions or nonsense mutations in VHL, while individuals with type 2 tend to have missense mutations.5,6,7

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation in symptomatic individuals and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular confirmation of a diagnosis may help avoid unnecessary testing and procedures, and allow for appropriate anticipatory guidance and medical surveillance. When the clinical diagnosis of VHL disease is confirmed by genetic testing, implementation of periodic screening has led to early detection of tumors, timely intervention, and improved outcome for individuals affected with this disorder.

VHL genetic testing could be considered for the following:

  • Any individual with suspected VHL disease who does not meet clinical criteria
  • Any asymptomatic child with a parent known to have a pathogenic VHL mutation
  • Any individual with a family history of VHL disease
  • Any individual with a clinical diagnosis of VHL disease interested in pursuing preimplantation genetic diagnosis or prenatal testing for this condition
Test Description 

VHL coding exons 1-3 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-3. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.8  Gross deletion/duplication analysis of VHL using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

At least 90% of individuals meeting the clinical criteria for VHL disease are expected to have a pathogenic mutation identifiable by gene sequencing and deletion/duplication analyses (clinical sensitivity). Ambry’s VHL testing can detect >99.9% of described mutations in the gene, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Since tumors associated with VHL disease have been reported in children as young as 4 years of age, testing of asymptomatic children under the age of 18 years is appropriate to consider when the disease-causing mutation in an affected parent is known. Please call an Ambry Genetic Counselor at (949) 900-5783 to discuss your case.

Turnaround Time 
2606 VHL Gene Sequence and Deletion/Duplication Analysis 14 - 21 


  1. Maher ER, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991; 28:443-447.
  2. Latif F, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993; 260(5112):1317-1320.
  3. Gnarra JR, et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet.
  4. Shuin T, et al. Von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol. 2006;36(6):337-343.
  5. Neumann HP, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466.
  6. Maher ER, et al. Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. J Med Genet. 1996;33:328-332.
  7. Stebbins CE, et al. Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function. Science. 1999;284:455–461.
  8. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.