Test Catalog

Test Id : VHLE

VHL Gene, Erythrocytosis, Mutation Analysis, Varies

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

Diagnosis of suspected JAK2-negative VHL-related erythrocytosis associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit

Method Name
A short description of the method used to perform the test

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

NY State Available
Indicates the status of NY State approval and if the test is orderable for NY State clients.


Reporting Name
Lists a shorter or abbreviated version of the Published Name for a test

VHL Gene Erythrocytosis Mutations

Lists additional common names for a test, as an aid in searching

Chuvash polycythemia

Hereditary Erythrocytosis

VHL (von Hippel-Lindau) Gene

Specimen Type
Describes the specimen type validated for testing


Specimen Required
Defines the optimal specimen required to perform the test and the preferred volume to complete testing

Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations.


This test is only available as a reflex from the HEMP / Hereditary Erythrocytosis Mutations. VHLE is not a single orderable test.

Specimen Minimum Volume
Defines the amount of sample necessary to provide a clinically relevant result as determined by the Testing Laboratory

Blood: 1 mL

Reject Due To
Identifies specimen types and conditions that may cause the specimen to be rejected

All specimens will be evaluated by Mayo Clinic Laboratories for test suitability.

Specimen Stability Information
Provides a description of the temperatures required to transport a specimen to the performing laboratory, alternate acceptable temperatures are also included

Specimen Type Temperature Time Special Container
Varies Ambient (preferred)

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

Diagnosis of suspected JAK2-negative VHL-related erythrocytosis associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit

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

Erythrocytosis (ie, increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (ie, polycythemia vera, or secondary, in response to increased serum erythropoietin levels). Secondary erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other Epo-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be suspected.


Unlike polycythemia vera, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis that has been present since birth. A small subset of cases is associated with pheochromocytoma and paraganglioma formation. It is caused by mutations in several genes, including VHL, and may be inherited in either an autosomal dominant or autosomal recessive manner. A family history of erythrocytosis would be expected in these cases, although it is possible for new mutations to arise in an individual.


The genes coding for hemoglobin, hemoglobin-stabilization proteins (2,3 bisphosphoglycerate mutase: BPGM), the erythropoietin receptor (EPOR), and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and VHL can result in hereditary erythrocytosis (see Table). High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF, PHD, and VHL typically have normal p50 results. The true prevalence of hereditary erythrocytosis causing mutations is unknown.


Genes Associated with Hereditary Erythrocytosis



Serum Epo


JAK2 V617F




JAK2 exon 12






Decreased to normal level




Normal level




Normal level


Beta Globin


Normal level to increased


Alpha Globin


Normal level to increased




Normal level to increased




Normal to increased



The oxygen-sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF), which regulates RBC mass. A heterodimer protein comprised of alpha and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen becomes a substrate-mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation does not take place and the alpha protein component is available to dimerize with a HIF-beta subunit. The heterodimer then induces transcription of many hypoxia response genes including EPO, VEGF, and GLUT1.


HIF-alpha is regulated by von Hippel-Lindau (VHL) protein-mediated ubiquitination and proteasomal degradation, which requires prolyl hydroxylation of HIF proline residues. Mutations resulting in altered VHL proteins can lead to familial erythrocytosis, type 2 (ECYT2; OMIM 263400). ECYT2 is a clinically heterogeneous disorder characterized by congenital erythrocytosis with or without high serum EPO levels, venous and arterial thrombosis, and pulmonary hypertension that can manifest as early as infancy but more typically into adulthood. An increased risk for tumors associated with von Hippel-Lindau syndrome, which is also caused by mutations in the VHL gene, has not been observed.

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.

Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations.


An interpretive report will be provided.

Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

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

This test does not provide a serum erythropoietin (Epo) level. If Epo testing is desired, see EPO / Erythropoietin (EPO), Serum.


Polycythemia vera and acquired causes of erythrocytosis should be excluded before ordering this evaluation.


This test is not intended for prenatal diagnosis.


This test will not detect somatic or gonadal mosaicism.


Certain sequence alterations have no clinical manifestations and, in essence, are clinically benign. Correlation with all relevant clinical information is necessary to provide appropriate patient care.


Some individuals who have involvement of the VHL gene may have a pathogenic variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of VHL disease. For predictive testing of asymptomatic individuals, it is important to first document the presence of a pathogenic gene variant in an affected family member.


Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.


In some cases, DNA variants of undetermined significance may be identified. Rarely, sequence variants 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. If results obtained do not match the clinical findings, additional testing should be considered.


Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common benign variants identified for this patient are available upon request.

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 pathogenic variants. These results are in agreement with published estimates of pathogenic variant rates of 29% to 61% for von Hippel-Lindau (VHL) in cRCC. Additionally, 2 specimens with known variants were tested. Sequences were 100% concordant with published data. Both inter- and intra-assay testing showed 100% consistency in sequencing. Fifteen normal specimens tested; all showed 100% normal sequences.

Clinical Reference
Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-423

2. Online Mendelian inheritance in Man-OMIM. Available at http://www.omim.org/entry/263400

3. Bento C, Percy M, Gardie B, et al: Genetic basis of congenital erythrocytosis: mutation update and online databases. Hum Mutat 2014;35(1):15-26

4. Pastore Y, Jedlickova K, Guan Y, et al: Mutations of von Hippel-Lindau tumor-suppressor gene and congenital polycythemia. Am J Hum Genet 2003;73(2):412-419

5. Merchant SH, Oliveira JL, Hoyer JD, et al: Molecular Diagnosis. In Hematopathology. Second edition, Series editor John Goldblum. Edited by ED His. Churchill Livingstone. Hematopathology: A Volume in Foundations in Diagnostic Pathology Series. 2012

Method Description
Describes how the test is performed and provides a method-specific reference

Bidirectional sequence analysis was performed to test for the presence of sequence variants in the three coding exons and intron/exon boundaries of the VHL gene (GenBank accession number NM_000551; build GRCh37 [hg19]).

PDF Report
Indicates whether the report includes an additional document with charts, images or other enriched information


Day(s) Performed
Outlines the days the test is performed. This field reflects the day that the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time before the test is performed. Some tests are listed as continuously performed, which means that assays are performed multiple times during the day.


Report Available
The interval of time (receipt of sample at Mayo Clinic Laboratories to results available) taking into account standard setup days and weekends. The first day is the time that it typically takes for a result to be available. The last day is the time it might take, accounting for any necessary repeated testing.

14 to 20 days

Specimen Retention Time
Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded

Whole Blood: 2 weeks (if available) Extracted DNA: 3 months

Performing Laboratory Location
Indicates the location of the laboratory that performs the test


Several factors determine the fee charged to perform a test. Contact your U.S. or International Regional Manager for information about establishing a fee schedule or to learn more about resources to optimize test selection.

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  • Prospective clients should contact their account representative. For assistance, contact Customer Service.

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 instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR) product.

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

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 Clinic Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.

CPT codes are provided by the performing laboratory.

81404-VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), full gene sequence

LOINC® Information
Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the order and results codes of this test. LOINC values are provided by the performing laboratory.

Test Id Test Order Name Order LOINC Value
VHLE VHL Gene Erythrocytosis Mutations 82528-1
Result Id Test Result Name Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
37886 Known Mut Reason for Referral 42349-1
37840 Result Summary 50397-9
37841 Result 82939-0
37842 Interpretation 69047-9
37843 Additional Information 48767-8
37844 Specimen 31208-2
37845 Source 31208-2
37846 Released By 18771-6

Test Setup Resources

Setup Files
Test setup information contains test file definition details to support order and result interfacing between Mayo Clinic Laboratories and your Laboratory Information System.

Excel | PHP Pdf | CMS Pdf

Sample Reports
Normal and Abnormal sample reports are provided as references for report appearance.

Normal Reports | Abnormal Reports

SI Sample Reports
International System (SI) of Unit reports are provided for a limited number of tests. These reports are intended for international account use and are only available through MayoLINK accounts that have been defined to receive them.

SI Normal Reports | SI Abnormal Reports