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Test Catalog

Test ID: PRCNG    
PROCR Gene, Next-Generation Sequencing, Varies

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

Ascertaining a pathogenic alteration in the PROCR gene in patients with recurrent unprovoked venous thromboembolism (VTE)before the age of 40, a strong family history of unexplained and unprovoked VTE, and prior genetic testing for more common genetic variants associated with thrombophilia that does not correlate with the severity of the patient’s thrombophilia or clinical presentation

 

This test is not intended for prenatal diagnosis

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test detects alterations in the PROCR gene associated with increased risk for venous thromboembolism.

 

The gene target for this test is:

Gene name (transcript): PROCR (GRCh37 [hg19] NM_006404)

Chromosomal location: 20q11.22

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

No screening tests exist for defects in PROCR. A set of clinical guidelines from the British Society for Haematology on testing for heritable thrombophilia is freely available.(1) A genetic consultation is strongly recommended prior to ordering PROCR sequencing.

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

Venous thromboembolism (VTE) can describe: 1) a deep vein thrombosis (DVT), characterized by leg pain or tenderness typically in only one thigh or calf, leg swelling, skin that feels warm to the touch, and reddish discoloration or streaks, or 2) a pulmonary embolism (PE), characterized by unexplained shortness of breath, rapid breathing, chest pain under the rib cage, fast heart rate, and light headedness or passing out.

 

VTEs affect about an estimated 900,000 individuals in the US per year.(2) While most individuals who experience a VTE do so only once in their life, some individuals may experience recurrent thrombotic episodes or have close relatives who do. The tendency to thrombose, sometimes referred to as thrombophilia or hypercoagulability, is considered a multifactorial disorder with many different factors increasing the risk for abnormal clotting. Thrombophilia is more likely to happen in people who are older, obese or overweight, and have conditions that promote blood coagulation like cancer or lupus. Other causes of acquired (non-genetic) thrombophilia include recent surgery, trauma, fractures, hospital or nursing home confinement, varicose veins, neurological disease with leg paresis, chronic renal disease, oral contraceptive use and hormone therapy, pregnancy and the post-partum period.(2) Less commonly, certain alterations in genes involved in blood coagulation may also increase the risk for thrombosis. A genetic cause for increased VTE may be considered in situations where a VTE occurs before the age of 40, is recurrent, occurs in multiple closely-related family members, and occurs in unusual locations in the body such as the portal, hepatic, mesenteric, or cerebral veins.  

 

The PROCR gene encodes for endothelial cell protein C receptor (EPCR), a transmembrane protein that plays a crucial role in the negative regulation of blood coagulation by increasing protein C activation five- to 20 fold via the thrombin-thrombomodulin complex.(3) Activated protein C (APC) then down regulates thrombin generation by inactivating factor VIIIa and factor Va.  Rare alterations in the PROCR gene may increase the risk of thrombosis, especially in carriers of other prothrombotic alterations, by an unknown amount. As a whole, the PROCR gene and alterations in it are not well characterized and thus genetic testing has limited clinical utility. As of January 2019, only 3 missense alterations and a single nucleotide polymorphism (SNP) in the 5’ untranslated region (5’UTR) in PROCR are reported to be associated with increased risk for venous thromboembolism in the Human Gene Mutation Database (HGMD Professional 2018.4). The prevalence of individuals with pathogenic alterations in the PROCR gene in the general population or among individuals with VTE is unknown.

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 interpretative report will be provided

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

 

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

 

Consultations with the Mayo Clinic Special Coagulation Clinic, Molecular Hematopathology Laboratory or Thrombophilia Center are available for DNA diagnosis cases. This may be especially helpful in complex cases or in situations where the diagnosis is atypical or uncertain.

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

Clinical:

Some individuals may have a mutation that is not identified by the methods performed. The absence of a mutation, therefore, does not eliminate the possibility of an increased risk of venous thromboembolism. This assay does not distinguish between germline and somatic alterations, particularly with variant allele frequencies (VAF) significantly lower than 50%. 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.

 

Technical Limitations:

Next-generation sequencing (NGS) may not detect all types of genetic variants. Additionally, rare polymorphisms may be present that could lead to false negative or positive results. Therefore test results should be interpreted in the context of activity and antigen measurements, clinical findings, family history, and other laboratory data. If results do not match clinical findings, consider alternative methods for analyzing these genes, such as Sanger sequencing or large deletion/duplication analysis. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If multiple alterations are identified, NGS is not able to distinguish between alterations that are found in the same allele ("in cis") and alterations found on different alleles ("in trans"). This limitation may complicate diagnosis or classification and has implications for inheritance and genetic counseling. To resolve these cases, molecular results must be correlated with clinical history, activity and antigen measurements, and/or family studies.

 

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 polymorphisms identified for this patient are available upon request.

 

Reclassification of Variants Policy: At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

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

1. Baglin T, Gray E, Greaves M, et al: Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220

2. Heit, JA: The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol. 2008;28(3):370-372

3. Stearns-Kurosawa DJ, Kurosawa S, Mollica JS: The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci USA. 1996;93(19):10212-6

4. Bouwnes EA, Stavenuiter F, Mosnier LO: Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway. J Thromb Haemost. 2013;11 Suppl 1:242-253

5. Nayak RC, Sen P, Ghosh S, et al: Endothelial cell protein C receptor cellular localization and trafficking: potential functional implications. Blood. 2009;114(9):1974-1986

6. Medina R, Navarro S, Estelles A, et al: Polymorphisms in the endothelial protein C receptor gene and thrombophilia. Thromb Haemost. 2007;98(3):564-569

7. Mohan Rao LV, Esmon CT, Pendurthi UR: Endothelial cell protein C receptor: a multiliganded and multifunctional receptor. Blood. 2014;124(10):1553-1562

8. Wu C, Dwivedi D, Pepler L, et al: Targeted Gene Sequencing Identifies Variants in the Protein C and Endothelial Protein C Receptor Genes in Patients With Unprovoked Venous Thromboembolism. Arterioscler Thromb Vasc Biol. 2013;33(11):2674-2681

9. Gleeson E, O’Donnell J, Preston R: The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling. Cell Mol Life Sci. 2012;69(5):717-726

Special Instructions Library of PDFs including pertinent information and forms related to the test