Test Catalog

Test ID: PCNGS    
Protein C Deficiency, PROC Gene, Next-Generation Sequencing, Varies

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

Ascertaining a pathogenic alteration in the PROC gene of patients with congenital protein C deficiency

 

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 pathogenic alterations in the PROC gene to delineate the underlying molecular defect in a patient with a laboratory diagnosis of protein C deficiency.

 

The gene target for this test is:

Gene name (transcript): PROC (GRCh37 [hg19] NM_000312)

Chromosomal location: 2q14.3

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

The clinical workup for protein C deficiency includes special coagulation testing for protein C activity (CFX / Protein C Activity, Plasma).

 

Genetic testing for protein C deficiency is indicated if:

-Protein C activity is reduced (<75% of normal)

-Acquired causes of protein C deficiency have been excluded (eg, vitamin K deficiency, oral anticoagulation with coumarin compounds, liver disease, intravascular coagulation and fibrinolysis/disseminated intravascular coagulation: ICF/DIC)

 

If protein C activity is low, protein C antigen testing (PCAG / Protein C Antigen, Plasma) helps to distinguish between type I and type II deficiencies.

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

Protein C is a vitamin K-dependent plasma glycoprotein synthesized in the liver. After secretion, protein C circulates in blood mostly in its inactive form until cleaved at residues Arg211-Leu212 to form activated protein C. Activated protein C and its cofactor, protein S, act as a potent anticoagulant by cleaving and inactivating procoagulant factors VIIIa and Va. A deficiency of protein C results in impairment of the ability to control coagulation through the inactivation of procoagulant factors, factor Va and factor VIIIa, leading to an increased risk of venous thrombosis. While protein C deficient individuals are 7 to 10 times more likely to develop venous thromboembolism (VTE), 3% to 9% of these individuals actually develop a VTE, and the annual risk of VTE is between 0.4% and 1.0% per year.(1)

 

Congenital protein C deficiency is classified into two types. Type I deficiency is characterized by decreased protein synthesis or increased intracellular protein degradation that lead to lower levels of protein C in blood. Type I deficiency accounts for about 75% of all cases of congenital protein C deficiency. Type II deficiency is characterized by dysfunctional protein C that is produced in normal amounts. There appears to be no clinical differences between type I and type II phenotypes. Protein C antigen testing (PCAG / Protein C Antigen, Plasma) is helpful to distinguish between type I and type II deficiencies and in cases where genetic testing results yield variants of uncertain significance (VUS).

 

The PROC gene encodes for protein C. Pathogenic alterations in the gene can cause congenital protein C deficiency. Congenital protein C deficiency is inherited as an autosomal dominant disorder but with variable penetrance. Both men and women can be affected. The estimated prevalence of protein C deficiency ranges from 200 to 400 per 100,000. Individuals who are heterozygous for a pathogenic PROC alteration are at increased risk for VTE and warfarin-induced skin necrosis. The co-inheritance of additional thrombotic risk factors, eg, factor V Leiden, can compound this risk, leading to a clinically significant disorder. Homozygosity or compound heterozygosity for pathogenic alterations in the PROC gene is associated with severe protein C deficiency, which presents in infancy as the development of cerebral vein thrombosis or neonatal pupura fulminans (ie, widespread cutaneous hemorrhage and tissue death due to thrombosis of the microvascular.) These infants typically have protein C levels that virtually undetectable. Severe protein C deficient patients with very low but detectable protein C levels typically present with thromboembolic disease during early childhood or adulthood.(2)

 

Causes of acquired (non-genetic) protein C deficiency that should be excluded prior to genetic testing include vitamin K deficiency, oral anticoagulation with coumarin compounds, liver disease, and intravascular coagulation and fibrinolysis/disseminated intravascular coagulation (ICF/DIC).

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

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, and 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 protein C deficiency. 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.

 

If there is a family history of protein C deficiency, it is often useful to test first-degree family members to help establish the clinical significance of variants of unknown significance.

 

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 false-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. Varga EA, Kujovich JL: Management of inherited thrombophilia: guide for genetics professionals. Clin Genet 2012;81:7-17

2. Heleen van Ommem C, Middeldorp S: Thrombophilia in childhood: to test or not to test. Semin Thromb Hemost 2011;37(7):794-801

3. Reitsma PH, Bernardi F, Doig RG, et al: Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995;73:876-879

4. Kottke-Marchant K, Comp P: Laboratory issues in diagnosing abnormalities of protein C, thrombomodulin, and endothelial cell protein C receptor. Arch Pathol Lab Med 2002;126:1337-1348

5. Cooper PC, Hill M, Maclean RM: The phenotypic and genetic assessment of protein C deficiency. Int J Lab Hematol 2012;34:336-346

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

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