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Protein S Deficiency via the PROS1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9901 PROS1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9901PROS181479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Protein S deficiency is a disorder that increases the risk of developing abnormal clots, especially deep vein thrombosis (DVT) within the legs and arms. Symptoms can range greatly from asymptomatic to life-threatening with severe clotting called purpura fulminans appearing shortly after birth. The vast clinical spectrum of Protein S deficiency is due to the influence of environmental factors including increased age, surgery, inactivity, pregnancy, smoking, and oral contraceptives as well as other genetic risk factors such as Factor V Leiden and Prothrombin 20210G>A (Varga and Kujovich 2012). Mild Protein S deficiency is the most prevalent form, occurring in about 1 in 500 individuals. Protein S deficiency may also be acquired through chronic inflammation, liver disease, and vitamin K deficiency, making diagnosis of the hereditable form more difficult (Marlar and Gausman 2011). Anticoagulation therapies such as warfarin have been used to mitigate clotting in patients with Protein S deficiency. Genetic testing may aid in differential diagnosis between inherited and acquired forms of Protein S deficiency as well as from protein C deficiency, antithrombin deficiency, and other hypercoagulability disorders (Varga and Kujovich 2012).

Genetics

Protein S deficiency is inherited in an autosomal dominant manner with variable penetrance due to mutations in the PROS1 gene. Rare compound heterozygous individuals typically have a severe form of the disease. Causative variants have been found throughout the PROS1 gene with missense, nonsense, insertions/deletions alterations, and splice site alterations representing 45%, 18%, 18%, and 14% of cases respectively (Gandrille et al. 2000; Biguzzi et al. 2005). Large deletions have been reported in a minority of cases (Pintao et al. 2009). Disease penetrance is incomplete, but linked to the degree of protein S activity loss. Thrombophilia risk is also increased through environmental factors and mutations in the F5 (Factor V Leiden), F2 (Prothrombin 20210), PROC, and SERPINC1 genes (Caspers M et al. 2012). Protein S functions as a cofactor for Protein C where together this complex functions to down regulate thrombin formation through degradation of pro-coagulation factors V and VIII (Marlar and Gausman 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

In a study of 53 patients with laboratory tests indicating Protein S deficiency (decreased Protein S activity or free antigen levels), mutation in the PROS1 gene was found in 38 (71%) (Biguzzi et al. 2005). Individuals with a familial history of thrombophilia identify a causative mutation in the F5, F2, SERPINC1, PROC, or PROS1 gene in about half of cases. Of those cases, PROS1 mutations represent between 1-3% of individuals with an identifiable hereditable cause for venous thromboembolism (Varga and Kujovich 2012).

Testing Strategy

This test provides full coverage of all coding exons of the PROS1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Patients with biochemical evidence showing decreased Protein S activity are ideal candidates as this is diagnostic for all three forms of Protein S deficiency. Individuals with type I form, representing ~80% cases, also have decreased free and total Protein S antigen levels. Type II individuals have unaffected Protein S antigen levels and type III only show decreases in free Protein S antigen. Patients with a strong family history of thrombophilia are also candidates for testing (Marlar and Gausman 2011). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PROS1.

Gene

Official Gene Symbol OMIM ID
PROS1 176880
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Biguzzi E, Razzari C, Lane DA, Castaman G, Cappellari A, Bucciarelli P, Fontana G, Margaglione M, D’Andrea G, Simmonds RE, Rezende SM, Preston R, et al. 2005. Molecular diversity and thrombotic risk in protein S deficiency: The PROSIT study. Human Mutation 25: 259–269. PubMed ID: 15712227
  • Caspers M, Pavlova A, Driesen J, Harbrecht U, Klamroth R, Kadar J, Fischer R, Kemkes-Matthes B, Oldenburg J. 2012. Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort. Thromb. Haemost. 108: 247–257. PubMed ID: 22627591
  • Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud MF, Dreyfus M, Matheron C, Gaussem P, Abgrall JF, Jude B, Sie P. 1995. Identification of 15 different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood 85: 130–138. PubMed ID: 11127877
  • Marlar RA, Gausman JN. 2011. Protein S abnormalities: A diagnostic nightmare. American Journal of Hematology 86: 418–421. PubMed ID: 21523802
  • Pintao MC, Garcia AA, Borgel D, Alhenc-Gelas M, Spek CA, Visser MCH de, Gandrille S, Reitsma PH. 2009. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Human Genetics 126: 449–456. PubMed ID: 19466456
  • Varga EA, Kujovich JL. 2012. Management of inherited thrombophilia: guide for genetics professionals. Clin. Genet. 81: 7–17. PubMed ID: 21707594

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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