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  • Test code: 01716
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae von Hippel-Lindau Syndrome Test

Test description

This test analyzes the VHL gene, which is associated with von Hippel-Lindau syndrome (VHL). This is a tumor predisposition condition characterized by the development of cysts and tumors throughout the body, hemangioblastoma, and an increased risk of developing clear cell renal carcinoma and pancreatic neuroendocrine tumors.

Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (1 gene)

Alternative tests to consider

VHL can also be ordered as part of a broader panel to test for different types of hereditary cancer, including pancreatic and other cancers. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.

  • von Hippel-Lindau syndrome (VHL)

Von Hippel-Lindau syndrome (VHL) is a hereditary tumor syndrome characterized by the development of cysts and tumors throughout the body. Although most of the tumors are benign, individuals with VHL have an increased risk of several types of cancer, including renal carcinoma and pancreatic neuroendocrine tumors. A hallmark feature of the condition is the development of a type of benign tumor made of blood vessels, called a hemangioblastoma. Cerebellar hemangioblastomas are associated with headache, vomiting, and gait abnormalities. Spinal hemangioblastomas are associated with pain and sensory motor loss. Retinal hemangioblastomas can cause blindness. Other tumor types associated with VHL include pheochromocytomas on the adrenal glands, which cause excess adrenaline production and endolymphatic sac tumors in the inner ear that can cause hearing loss.

Essentially everyone with VHL will manifest symptoms of the condition by late adulthood. VHL is also highly variable, meaning individuals with VHL may present differently, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant.

Tumor typeLifetime risk
Pheochromocytoma 10%-20%
Renal cell carcinoma 24%-45%
Pancreatic neuroendocrine tumors 5%-17%
Central nervous system hemangioblastoma 60%-80%

Approximately 90%-100% of affected individuals have an identifiable pathogenic variant in the VHL gene.

VHL is inherited in an autosomal dominant pattern. Approximately 80% of affected individuals inherit VHL from a parent, but 20% of cases are the result of a spontaneous de novo mutation in the VHL gene.

The prevalence of VHL is estimated at 1 in 36,000 individuals.

Analysis of the VHL gene may be considered in individuals who have a personal and/or family history of the following:

  • hemangioblastomas
  • multiple renal cysts
  • renal cell carcinoma
  • pheochromocytoma
  • endolymphatic sac tumors

Clinical diagnostic criteria for VHL have also been proposed:

  1. van Leeuwaarde RS, et al. Von Hippel-Lindau Syndrome. 2000 May 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1463/ PMID: 20301636
  2. Maher, ER, et al. von Hippel-Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 2011; 19(6):617-23. doi: 10.1038/ejhg.2010.175. PMID: 21386872
  3. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  4. Wind, JJ, Lonser, RR. Management of von Hippel-Lindau disease-associated CNS lesions. Expert Rev Neurother. 2011; 11(10):1433-41. doi: 10.1586/ern.11.124. PMID: 21955200
  5. Maher, ER, et al. Von Hippel-Lindau disease: a genetic study. J. Med. Genet. 1991; 28(7):443-7. doi: 10.1016/0140-6736(91)91711-3. PMID: 1895313
  6. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  7. Cassol, C, Mete, O. Endocrine manifestations of von Hippel-Lindau disease. Arch. Pathol. Lab. Med. 2015; 139(2):263-8. doi: 10.5858/arpa.2013-0520-RS. PMID: 25611110
  8. Ben-Skowronek, I, Kozaczuk, S. Von Hippel-Lindau Syndrome. Horm Res Paediatr. 2015; :None. doi: 10.1159/000431323. PMID: 26279462
  9. National Library of Medicine, Genetics Home Reference: Von Hippel-Lindau Syndrome. http://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome Accessed September 2019.
  10. American Society of Clinical Oncology, Cancer.Net: Von Hippel-Lindau Syndrome. http://www.cancer.net/cancer-types/von-hippel-lindau-syndrome Accessed September 2019.

Management recommendations and guidelines have been proposed for individuals with VHL. Please refer to:

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
VHL NM_000551.3