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. American Society of Clinical Oncology, Cancer.Net: Von Hippel-Lindau Syndrome. Accessed June 2015.
  2. Ben-Skowronek, I, Kozaczuk, S. Von Hippel-Lindau Syndrome. Horm Res Paediatr. 2015; :None. doi: 10.1159/000431323. PMID: 26279462
  3. 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
  4. Frantzen, C, et al. Von Hippel-Lindau Syndrome. 2000 May 17. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: PMID: 20301636
  5. 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
  6. 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
  7. 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
  8. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  9. National Library of Medicine, Genetics Home Reference: Von Hippel-Lindau Syndrome. Accessed June 2015.
  10. 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

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

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