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Test ID: VHLSP    
Von Hippel-Lindau (VHL) Gene, Full Gene Analysis

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnosis of suspected von Hippel-Lindau (VHL) disease


Screening presymptomatic members of VHL families


Diagnosis of hereditary erythrocytosis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

von Hippel-Lindau (VHL) disease is an autosomal dominant cancer syndrome with a birth incidence of approximately 1 in 36,000 livebirths. It predisposes affected individuals to the development of mainly 5 different types of neoplasms: retinal angioma (>90% penetrance), cerebellar hemangioblastoma (CHB) (>80% penetrance), clear-cell renal cell carcinoma (cRCC) (approximately 75% penetrance), spinal hemangioblastoma (SHB) (approximately 50% penetrance), and pheochromocytoma (PC) (approximately 30% penetrance). Angiomas in other organs, pancreatic cysts/adenomas/carcinomas, islet cell tumors, and endolymphatic sac tumors can also occur, but at much lower frequencies. VHL-related tumors start presenting at approximately 10 to 15 years of age (retinal angioma may present earlier), except for cRCC, which lags about a decade behind. For each tumor type, the incidence rates rise steadily, albeit at different slopes, throughout life.


VHL disease is caused by germline loss-of-function point mutations, deletions or insertions (approximately 80% of cases), or large germline deletions (approximately 20% of cases) of 1 copy of the VHL gene. Approximately 20% of cases are due to new mutations. VHL codes for a protein that is involved in ubiquitination and degradation of a variety of other proteins, most notably hypoxia-inducible factor (HIF). HIF induces expression of genes that promote cell survival and angiogenesis under conditions of hypoxia. It is believed that diminished HIF degradation due to inactive VHL protein causes the tumors in VHL disease. Tumors form when the remaining intact copy of VHL is somatically inactivated in target tissues. Sporadic cRCC, unrelated to VHL disease, also shows somatic deletions, mutations, or aberrant methylation in 80% to 100% of cases.


Retinal angioma, CHB, and SHB cause morbidity, and some mortality, through pressure on adjacent structures and through retinal or subarachnoid hemorrhages. VHL-related cRCC and PC follow a similar clinical course as their sporadic counterparts, with substantial morbidity and mortality. Early detection of VHL-related tumors can reduce these adverse outcomes, and surveillance of affected individuals is therefore widely advocated. Genetic testing is the most accurate way to identify presymptomatic individuals, who can then be entered into a surveillance program.


Genetic testing might also predict the types of tumors that will occur, and can, therefore, be used to individualize surveillance programs. Certain combinations of the 5 major VHL-tumors cluster in VHL families. This observation has led to a phenotype-based classification of VHL syndrome into type 1 (cRCC with any combination of retinal angioma, CHB, or SHB), type 2A (PC with any combination of retinal angioma, CHB, or SHB), type 2B (both cRCC and PC, with any combination of retinal angioma, CHB, or SHB) and type 2C (isolated PC). Type 1 accounts for 60% to 80% of cases, while type 2C is exceedingly rare. However, phenotyping is only accurate in large kindreds. In smaller kindreds, genetic testing can assist in tailoring follow-up to patient needs. For example, missense mutations, particularly those affecting surface amino acids involved in maintaining the surface structural integrity of VHL protein, are strongly associated with PC. By contrast, nonsense or frameshift mutations that disrupt overall VHL protein structure and large deletions are associated with early clinical presentation and increased age-related risks for retinal angioma and cRCC.


Additionally, mutations distinct from those associated with VHL syndrome can cause hereditary erythrocytosis or polycythemia. Cases of VHL disease and erythrocytosis are largely mutually exclusive, and patients who present with erythrocytosis do not typically develop the neoplasms discussed above, although they are sometimes associated with varicose veins and vertebral hemangiomas. Erythrocytosis due to mutations in VHL, is caused by germ line homozygous or compound heterozygous point mutations, and is inherited in an autosomal recessive manner. These patients usually have a markedly high erythropoietin level in the presence of an elevated hematocrit.  Erythrocytosis due to the germ line homozygous missense mutation at nucleotide 598C->T, p.R200W in the VHL gene has been found endemically in the Chuvash region of Russia, leading individuals with this mutation to be labeled as having Chuvash polycythemia (CP) although further studies have determined that this mutation can be found in other ethnic groups as well. These patients are at an increased risk to develop cerebrovascular and embolic complications. Heterozygous carriers are typically unaffected.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Rarely, unknown polymorphisms in primer- or probe-binding sites can result in false-negative test results (DNA sequencing) or either false-positive or false-negative results (multiplex ligation-dependent probe amplification [MLPA]; deletion screening), due to selective allelic drop-out. False-negative or false-positive results can occur in MLPA deletion screening assays due to poor DNA quality.


In addition to disease-related probes, the MLPA technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.


If the specimen is from a tumor (frozen tissue), in particular a sporadic tumor (rather than a von Hippel-Lindau-related tumor), 1 of the alleles might be inactivated by promoter hypermethylation. Our assay does not detect hypermethylation.


This test does not reliably detect large gene deletions in formalin-fixed paraffin-embedded tissues.

Supportive Data

Accuracy of this assay was assessed by sequencing 25 specimens from patients with clear-cell renal cell carcinoma (cRCC) of which 6 (24%) showed mutations. These results are in agreement with published estimates of mutation rates of 29% to 61% for von Hippel-Lindau (VHL) in cRCC. Additionally, 2 specimens with known mutations were tested. Sequences were 100% concordant with published data. Both inter- and intraassay testing showed 100% consistency in sequencing. Fifteen normal specimens tested; all showed 100% normal sequences.


Deletion detection was tested using 5 specimens with known sequences. Three of the 5 had large deletions. All specimens showed 100% concordance with published results and with inter- and intra-assay testing. An additional study was conducted in which 50 normal specimens were tested for deletions of VHL. All specimens were normal.

Clinical Reference Provides recommendations for further in-depth reading of a clinical nature

1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300

2. Online Mendelian inheritance in Man-OMIM. Available from URL:

3. Universal Mutation database-UMD-VHL mutations database page. Available from URL:

4. Maher ER, Kaelin WG Jr: von Hippel-Lindau disease (Reviews in Molecular Medicine). Medicine 1997;76:381-391

5. Pack SD, Zbar B, Pak E, et al: Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization. Cancer Res 1999;59:5560-5564

6. Richards FM: Molecular pathology of von Hippel-Lindau disease and the VHL tumor suppressor gene. Expert Rev Mol Med 2001;3:1-27

7. Hes FJ, Hoppener JW, Lips CJ: Clinical review 155: pheochromocytoma in von Hippel-Lindau disease. J Clin Endocrinol Metab 2003;88:969-974

8. Ong KR, Woodward ER, Killick P, et al: Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat 2007;28:143-149

Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test