Test Code GNPRC Protein C Deficiency, PROC Gene, Next-Generation Sequencing, Varies

Ordering Guidance

This test should only be considered if clinical and family history, initial coagulation screens, and initial protein C activity and antigen tests indicate a diagnosis of antithrombin deficiency (see Testing Algorithm). This test does not measure protein C activity or antigen levels.

For assessment of protein C activity, order CFX / Protein C Activity, Plasma. If protein C activity is low, protein C antigen testing could help distinguish between type I and type II deficiencies; order PCAG / Protein C Antigen, Plasma.

For assessment of protein C antigen, order PCAG / Protein C Antigen, Plasma.

If genetic testing for hereditary blood clotting disorders using a larger panel is desired, a 16-gene comprehensive thrombosis panel is available; order GNTHR / Thrombosis Disorders, Comprehensive Gene Panel, Next-Generation Sequencing, Varies.

Testing for the PROC gene as part of a customized panel is available. For more information see CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies.

Targeted testing for familial variants (also called site-specific or known variants testing) is available for variants identified in the PROC gene. See FMTT / Familial Variant, Targeted Testing, Varies. To obtain more information about this testing option, call 800-533-1710.

Shipping Instructions

Specimen preferred to arrive within 96 hours of collection.

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

Specimen Type: Whole blood

Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD)

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 Information: Ambient (preferred) 4 days/Refrigerated

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 an Coagulation Test Request (T753) with the specimen.

Secondary ID

619173

Useful For

Evaluating protein C deficiency in patients with a personal or family history suggestive of this hereditary thrombophilia

Confirming a diagnosis of autosomal dominant protein C deficiency with the identification of a known or suspected disease-causing alteration in the PROC gene

Confirming a diagnosis of autosomal recessive severe protein C deficiency with the identification of homozygous or compound heterozygous disease-causing alteration(s) in the PROC gene

Determining the disease-causing alteration(s) within the PROC gene to delineate the underlying molecular defect in a patient with a laboratory diagnosis of protein C deficiency

Prognosis and risk assessment based on the genotype-phenotype correlations

Ascertaining the variant status of family members related to an individual with a confirmed PROC variant for the purposes of informing clinical management and genetic counseling

Carrier testing for close family members of an individual with a diagnosis of autosomal recessive severe protein C deficiency

This test is not intended for prenatal diagnosis.

Testing Algorithm

The clinical workup for protein C deficiency should begin with special coagulation testing for protein C activity.

Genetic testing for protein C deficiency is indicated if:

-Protein C activity is less than 75% of normal (Note: reference range may vary depending on the locally established reference range)

-There is a clinical suspicion of hereditary thrombophilia and possible protein C deficiency due to family history or atypical clinical presentation

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

Method Name

Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing

Reporting Name

PROC Gene, Full Gene NGS

Specimen Type

Varies

Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Varies	Varies

Reject Due To

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

Clinical Information

Hereditary protein C deficiency is a rare inherited blood clotting disorder (thrombophilia) associated with germline variants in the PROC gene. Protein C is an important component of the bodyâ€™s natural anticoagulant system. A deficiency results in an unchecked clotting cascade and an increased risk of thromboembolism.(1)

Individuals who are heterozygous for a disease-causing variant in PROC have mild protein C deficiency, which is inherited in an autosomal dominant manner. Mild protein C deficiency is characterized by an increased risk for venous thromboembolism and warfarin-induced skin necrosis. The coinheritance of additional thrombotic risk factors (eg, factor V Leiden) can compound the clotting risk. The estimated prevalence of mild protein C deficiency is between 1 in 200 to 1 in 500.(1-3)

Homozygosity or compound heterozygosity for disease-causing variants in PROC is associated with severe protein C deficiency, which is extremely rare (estimated prevalence of 1 in 500,000 to 1 in 750,000) and is inherited in an autosomal recessive manner. This disorder typically presents with purpura fulminans and disseminated intravascular coagulation within 72 hours of birth but, occasionally, in later infancy. Infants with severe deficiency typically have protein C levels that are virtually undetectable.(1,2,4)

Several causes of acquired (nongenetic) protein C deficiency should be excluded prior to genetic testing, including vitamin K deficiency, oral anticoagulation with coumarin compounds, liver disease, and intravascular coagulation and fibrinolysis/disseminated intravascular coagulation.(2,5)

The British Society for Haematology provides guidelines regarding diagnosis, management, and laboratory testing for individuals with hereditary thrombophilias, including protein C deficiency.(6)

Reference Values

An interpretive report will be provided.

Interpretation

All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(7) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Method Description

Next-generation sequencing (NGS) and/or Sanger sequencing are performed to test for the presence of variants in coding regions and intron/exon boundaries of the PROC gene, as well as some other regions that have known disease-causing variants. The human genome reference GRCh37/hg19 build was used for sequence read alignment. At least 99% of the bases are covered at a read depth over 30X. Sensitivity is estimated at above 99% for single nucleotide variants, above 94% for deletions-insertions (delins) less than 40 base pairs (bp), above 95% for deletions up to 75 bp and insertions up to 47 bp. NGS and/or a polymerase chain reaction-based quantitative method is performed to test for the presence of deletions and duplications in the PROC gene.

There may be regions of the PROC gene that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences.(Unpublished Mayo method)

The reference transcript for PROC is NM_000312.3. Reference transcript numbers may be updated due to transcript re-versioning. Always refer to the final patient report for gene transcript information referenced at the time of testing. Confirmation of select reportable variants may be performed by alternate methodologies based on internal laboratory criteria.

Day(s) Performed