Test ID: VHLD
Von Hippel-Lindau (VHL) Deletion Detection
Secondary ID 
A test code used for billing and in test definitions created prior to November 2011
NY State Approved Indicates the status of NY State approval and if the test is orderable for NY State clients.
Useful For Suggests clinical disorders or settings where the test may be helpful
Diagnosis of suspected Von Hippel-Lindau disease
Screening presymptomatic members of Von Hippel-Lindau families
Tailoring optimal tumor-surveillance strategies for patients, when used in conjunction with phenotyping
Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.
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
Method Name A short description of the method used to perform the test
Polymerase Chain Reaction (PCR) Amplification/Deletion Detection by Multiplex Ligation-Dependent Probe Amplification (MLPA)
(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)
Reporting Name A shorter/abbreviated version of the Published Name for a test; an abbreviated test name
Aliases Lists additional common names for a test, as an aid in searching
Von Hippel Lindau familial cancer syndrome
Von Hippel Lindau tumor suppressor
Specimen Type Describes the specimen type needed for testing
Specimen Required Defines the optimal specimen. This field describes the type of specimen required to perform the test and the preferred volume to complete testing. The volume allows automated processing, fastest throughput and, when indicated, repeat or reflex testing.
Container/Tube: Lavender top (EDTA)
Specimen Volume: 3 mL
Collection Instructions: Send specimen in original tube.
Additional Information: Transfusions will interfere with testing for up to 4 to 6 weeks. DNA obtained from white cells may not provide useful information for patients who received a recent transfusion of blood that was not leukocyte-reduced. Wait 4 to 6 weeks until transfused cells have left the patient's circulation before drawing the patient's blood specimen for genotype testing.
Forms:
1. VHL Gene Testing Patient Information Sheet (Supply T641) in Special Instructions is required.
2. Informed Consent for Genetic Testing (Supply T576) in Special Instructions is required.
3. New York Clients- Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions
Specimen Minimum Volume Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.
Reject Due To Identifies specimen types and conditions that may cause the specimen to be rejected
| Hemolysis | Mild OK; Gross OK |
| Lipemia | Mild OK; Gross OK |
| Icterus | Mild OK; Gross OK |
| Other | NA |
Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the laboratory. Alternate acceptable temperature(s) are also included.
| Specimen Type | Temperature | Time |
|---|---|---|
| Whole Blood EDTA | Refrigerated (preferred) | |
| Ambient | ||
| Frozen | ||
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 1:36,000 live births. 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 or deletions/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 ubiquination and degradation of a variety of other proteins, most notable 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 an combination of retinal angioma, CHB, or SHB), type 2A (PC with an 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, in particular 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.
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 Hipple-Lindau (VHL); VHL-related tumor), 1 of the alleles might be inactivated by promoter hypermethylation. Our assay does not detect hypermethylation.
This test does not reliably detect deletions in formalin-fixed, paraffin-embedded tissues.
Absence of a deletion does not preclude the diagnosis of VHL unless a specific deletion has already been identified in an affected family member.
In the event of negative results by this technique, VHL sequencing (VHLSP/89083 Von Hippel-Lindau (VHL) Gene, Full Gene Analysis) should be considered to rule-out point mutations and small deletions/duplications.
Supportive Data
Accuracy of this test 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 for Von Hippel-Lindau (VHL) in cRCC of 29% to 61%. Additionally, 2 specimens with known mutations were tested. Sequences were 100% concordant with published data. Both inter- and intra-assay testing showed 100% consistency in sequencing. Fifteen normal samples tested all showed 100% normal sequences.
Deletion detection was tested using 5 samples 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 results 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: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193300
3. Universal Mutation database-UMD-VHL mutations database page. Available from URL: http://www.umd.be:2020/
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
Method Description Describes how the test is performed and provides a method-specific reference
Detection of large deletions in the VHL gene is accomplished by multiplexed ligation-dependent probe amplification and detection on Luminex beads specific to each exon.(Unpublished Mayo method)
Day(s) and Time(s) Test Performed Outlines the days and times the test is performed. This field reflects the day and time the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time required before the test is performed. Some tests are listed as continuously performed, which means assays are performed several times during the day.
Monday 8 a.m.
Analytic Time Defines the amount of time it takes the laboratory to setup and perform the test. This is defined in number of days. The shortest interval of time expressed is "same day/1 day," which means the results may be available the same day that the sample is received in the testing laboratory. One day means results are available 1 day after the sample is received in the laboratory.
Maximum Laboratory Time Defines the maximum time from specimen receipt at Mayo Medical Laboratories until the release of the test result
Specimen Retention Time Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Performing Laboratory Location The location of the laboratory that performs the test
Test Classification Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer's instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR), Investigation Use Only (IUO) product, or a Research Use Only (RUO) product.
CPT Code Information Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Medical Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
81403-Known familial variant, not otherwise specified, for gene listed in Tier 1 or Tier 2, DNA sequence analysis
LOINC® Code Information Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the result codes returned for this test or profile.
| Result ID | Reporting Name | LOINC Code |
|---|---|---|
| 31722 | Reason for Referral | 42349-1 |
| 31723 | Method | In Process |
| 31724 | Result | 34502-5 |
| 31725 | Interpretation | 69047-9 |
| 31726 | Comment | In Process |
| 31727 | Reviewed By | N/A |
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