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.

 

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)

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

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

Custom Sequence Capture and Targeted Next-Generation Sequencing (NGS) Followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing when appropriate

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

Yes

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

PROC Gene, Full Gene NGS

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

Congenital protein C deficiency

Hereditary thrombophilia

Hereditary thrombophilia due to protein C deficiency

Protein C

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.

 

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)

Specimen Type
Describes the specimen type validated for testing

Varies

Ordering Guidance

For assessment of protein C activity, order CFX / Protein C Activity, Plasma.

 

If protein C activity is low, consider protein C antigen testing to help distinguish between type I and type II deficiencies. Order PCAG / Protein C Antigen, Plasma.

Shipping Instructions

Ambient and refrigerated specimens must arrive within 7 days of collection, and frozen specimens must arrive within 14 days.

 

Collect and package specimen as close to shipping time as possible.

Necessary Information

Rare Coagulation Disorder Patient Information is required. Testing may proceed without the patient information, however, the information aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to fill out the form and send with the specimen.

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

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD) or light-blue top (3.2% sodium citrate)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability: Ambient (preferred)/Refrigerate/Frozen

 

Specimen Type: Extracted DNA

Container/Tube: 1.5- to 2-mL tube

Specimen Volume: Entire specimen

Collection Instructions:

1. Label specimen as extracted DNA and source of specimen.

2. Provide volume and concentration of the DNA.

Specimen Stability: Frozen (preferred)/Refrigerate/Ambient

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

Forms

1. Rare Coagulation Disorder Patient Information (T824) is required.

2. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

3. If not ordering electronically, complete, print, and send a Coagulation Test Request (T753) with the specimen.

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

Blood: 1 mL blood

Extracted DNA: 100 mcL at 50 ng/mcL concentration

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

Gross hemolysis OK
Gross lipemia OK

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) 7 days
Frozen 14 days
Refrigerated 7 days

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.

 

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)

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 2 types.

-Type I deficiency is characterized by decreased protein synthesis or increased intracellular protein degradation, which leads 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.

 

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 coinheritance 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 purpura 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 (nongenetic) 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.

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 variant that is not identified by the methods performed. The absence of a variant, 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 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 variants (ie, 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 alterations (ie, 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 Jan;81(1):7-17

2. Heleen van Ommem C, Middeldorp S: Thrombophilia in childhood: to test or not to test. Semin Thromb Hemost. 2011 Oct;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 May;73(5):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 Nov;126(11):1337-1348

5. Cooper PC, Hill M, Maclean RM: The phenotypic and genetic assessment of protein C deficiency. Int J Lab Hematol. 2012 Aug;34(4):336-346

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

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

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

Next-generation sequencing (NGS) and/or Sanger sequencing are performed.

 

Regions of homology, high guanine-cytosine (GC)-rich content, and repetitive sequences may not provide accurate sequence. Therefore, all reported alterations detected by NGS in these regions are confirmed by an independent reference method. However, this does not rule out the possibility of a false-negative result in these regions.

 

Sanger sequencing is used to confirm alterations detected by NGS when appropriate.(Unpublished Mayo method)

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

No

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.

Weekly

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.

21 to 28 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; DNA: Indefinitely

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

Rochester

Fees
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.

  • Authorized users can sign in to Test Prices for detailed fee information.
  • Clients without access to Test Prices can contact Customer Service 24 hours a day, seven days a week.
  • Prospective clients should contact their Regional Manager. 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. This test 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.

81479

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
PCNGS PROC Gene, Full Gene NGS 93815-9
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.
606407 PCNGS Result 50397-9
606408 Alterations Detected 82939-0
606409 Interpretation 69047-9
606410 Additional Information 48767-8
606411 Method 85069-3
606412 Disclaimer 62364-5
606413 Panel Gene List 48018-6
606414 Reviewed 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 | Create a 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