• 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




Associated disorders

The VHL gene is associated with autosomal dominant von Hippel-Lindau (VHL) syndrome (MedGen UID: 42458), and autosomal recessive familial erythrocytosis, type 2 (MedGen UID: 332974).

The VHL gene encodes a tumor-suppressor protein that acts as the substrate recognition component of an E3 ubiquitin ligase complex that targets other proteins (notably HIF, hypoxia inducible factor) for proteosomal degradation. Loss of VHL function results in the stabilization of these target proteins, leading to altered gene transcription, cell survival and proliferation, and vascularization.

Von Hippel-Lindau syndrome
MedGen UID: 42458

Clinical Condition
Von Hippel-Lindau syndrome (VHL) is a highly variable hereditary tumor syndrome with clinical symptoms developing with advancing age (PMID: 21386872). The condition is characterized by the development of cysts and tumors throughout the body. Although most tumors are benign, individuals with VHL have an increased risk of several types of cancer, including clear-cell renal cell carcinoma and pancreatic neuroendocrine tumors (PMID: 21386872, 20301636; American Society of Clinical Oncology. Von Hippel-Lindau syndrome. http://www.cancer.net/cancer-types/von-hippel-lindau-syndrome. Accessed July 2017; National Library of Medicine. Genetics Home Reference: Von Hippel-Lindau syndrome. https://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome. Accessed July 2017).

A hallmark feature of VHL is the development of central nervous system (CNS) hemangioblastomas (PMID: 20301636). Hemangioblastomas in the cerebellum, brainstem, and spinal cord occur in approximately 60-80% of affected individuals (PMID: 21386872). Cerebellar hemangioblastomas are associated with symptoms such as headache, vomiting, and gait abnormalities, while spinal hemangioblastomas are associated with pain and sensory motor loss (PMID: 20301636). CNS hemangioblastomas are benign and enlarge at a variable rate (PMID: 21386872).

Retinal hemangioblastomas are another common presenting feature of VHL and are found in approximately 70% of patients (PMID: 21386872, 20301636). Approximately half of individuals with VHL experience multiple and bilateral retinal lesions (PMID: 20301636). Retinal hemangioblastomas may be asymptomatic or result in vision loss (PMID: 20301636). The cumulative lifetime risk of vision loss is 35% among all individuals with a pathogenic variant in the VHL gene and 55% among those with retinal hemangioblastomas present by 50 years of age (PMID: 21386872).

Multiple pancreatic cysts typically develop with age and are present in most older affected individuals; however, these lesions rarely impair pancreatic function (PMID: 21386872, 20301636, 25611110). Pancreatic tumors occur in 5-10% of cases and are typically solid, non-secretory islet cell tumors (PMID: 21386872, 25611110). Pancreatic neuroendocrine tumors develop in approximately 5-17% of individuals with VHL (PMID: 21386872, 25611110).
Multiple renal cysts are common in VHL (PMID: 20301636, 21386872). While these cysts rarely compromise renal function, the epithelial lining may display pre-malignant features (PMID: 21386872). The estimated risk of renal cell carcinoma ranges from 40% to 70% (PMID: 20301636, 21386872).

Pheochromocytomas are also associated with VHL (PMID: 20301636). The overall risk of developing a pheochromocytoma is approximately 10-20% (PMID: 25611110, 19017755). Of the cases that develop a pheochromocytoma, the risk of malignant transformation is estimated to be less than 5% (PMID: 21386872, 25611110).

Endolymphatic sac tumors in the inner ear are seen in approximately 10-16% of individuals with VHL, and bilateral tumors are considered pathognomonic for the condition (PMID: 20301636, 21386872). Many are asymptomatic; however, hearing loss is the most common presenting feature (PMID: 21386872). Additional signs and symptoms include vertigo and tinnitus (PMID: 20301636, 21386872).

Other observed tumors include head and neck paragangliomas (0.5% of cases), and benign, typically asymptomatic epididymal cystadenomas, which occur in up to 60% of affected males (PMID: 21386872).

VHL has been categorized into two subtypes that are based on the likelihood of developing pheochromocytoma or renal cell carcinoma. These subtypes currently have no diagnostic or therapeutic value and are only used for academic purposes (PMID: 21386872):

  • VHL type 1 is generally associated with retinal and CNS hemangioblastomas, renal cell carcinoma, pancreatic cysts, and neuroendocrine tumors; however, the risk of pheochromocytomas is low.
  • VHL type 2 is associated with retinal angiomas, CNS hemangioblastomas, and a high risk of pheochromocytomas. VHL type 2 is further subdivided into types 2A, 2B, and 2C:
    • Type 2A has a low risk of renal cell carcinoma
    • Type 2B has a high risk of renal cell carcinoma
    • Type 2C only presents with pheochromocytoma

Despite this subtype categorization, genotype-phenotype correlations currently do not influence medical management recommendations (PMID: 21386872, 20301636; American Society of Clinical Oncology. Von Hippel-Lindau syndrome. http://www.cancer.net/cancer-types/von-hippel-lindau-syndrome. Accessed July 2017; National Library of Medicine. Genetics Home Reference: Von Hippel-Lindau syndrome. https://ghr.nlm.nih.gov/condition/von-hippel-lindau-syndrome. Accessed July 2017).

Gene Information
VHL is a tumor suppressor gene, meaning that it helps to control the rate of growth and cell division in the body. It is believed to act as a target recruitment subunit in the E3 ubiquitin ligase complex and is involved in transcriptional repression (UniProtKB – P40337 (VHL_HUMAN). http://www.uniprot.org/uniprot/P40337. Accessed July 2017). The risk of developing certain types of cancers may be increased if there is a pathogenic variant in this gene that prevents it from functioning normally.

VHL has autosomal dominant inheritance. This means that an individual with a pathogenic variant in the VHL gene has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, but approximately 20% can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it; PMID: 21386872, 25611110). However, that individual now has a 50% risk of passing it on to their future offspring.

Additionally, individuals with a pathogenic variant in VHL are carriers of familial erythrocytosis type 2 (FE2). FE2 is an autosomal recessive condition that occurs when an individual inherits a pathogenic VHL variant from each parent. This disorder is characterized by overproduction of red blood cells, which may cause such symptoms as headache, dizziness, nosebleeds, shortness of breath, and blood clots (PMID: 12844285, 11987242). There is a risk of FE2 in offspring only when both parents have a single pathogenic variant in VHL; in such cases, the risk of having an affected child is 25%.

Medical management guidelines and surveillance recommendations
Symptoms of VHL develop with age, and thus early diagnosis and management improve prognosis (PMID: 21386872). Individuals with VHL can benefit from seeking care in specialized, multidisciplinary clinics with experience and expertise in treating this condition (PMID: 21386872). The following evaluations are recommended in individuals diagnosed with VHL (PMID: 21386872, 20301636):

  • MRI scans of the head and/or spine every 12-36 months beginning at 16 years of age to assess for CNS hemangioblastomas and endolymphatic sac tumors
  • Annual ophthalmologic evaluation for retinal hemangioblastomas beginning at 1 year of age
  • Audiologic evaluation every 2-3 years beginning at age 5 for possible hearing loss associated with endolymphatic sac tumors
    • Annual examination if there is hearing loss, tinnitus, or vertigo
    • If repeated ear infections are present, MRI with contrast of the internal auditory canal using thin slices
  • Annual abdominal ultrasound or MRI scans beginning at age 16 years to assess for visceral lesions including renal cell carcinoma
    • While abdominal CT is more sensitive, MRI or ultrasound is preferred to avoid long-term radiation exposure
  • Annual blood pressure determination beginning at 1 year of age and 24-hour urine studies to measure catecholamine metabolites beginning at age 5 years

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic VHL variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding VHL are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow condition-specific screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: July 2017

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

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