Invitae Protein S Deficiency Test


Test description

Protein S deficiency is typically an adult-onset hereditary condition that is a result of pathogenic variants in the PROS1 gene. This disorder causes an increased risk of deep venous thrombosis, superficial thrombophlebitis, and pulmonary embolism.

Genetic testing of the PROS1 gene may establish or confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also enable testing and diagnosis of at-risk relatives.

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Primary panel (1 gene)


Alternative tests to consider

Testing for protein S deficiency is also included in the broader Invitae Hereditary Thrombophilia Panel. Depending on the individual’s clinical and family history, this broader panel may be appropriate and can be ordered at no additional charge.

Protein S deficiency

Protein S deficiency is an adult-onset condition that increases the risk of blood-clot formation. Protein S deficiency may be hereditary and due to pathogenic variants in PROS1, or acquired through hepatic disease or a vitamin K deficiency. This disorder is associated with an increased risk of developing blood clots in deep veins, especially in the legs (deep vein thrombosis), which can lead to the clots breaking off and blocking blood flow in other parts of the body like the lungs (where it would cause a pulmonary embolism). Approximately half of these events are unprovoked (i.e., they are not preceded by such typical transient risk factors as surgery, trauma, immobilization, air travel, pregnancy, or systemic hormonal contraception). Women with protein S deficiency also have an increased risk of miscarriage and other pregnancy complications.

Individuals with a pathogenic variant in both copies of their PROS1 gene can develop a rare, severe form of protein S deficiency that can cause a life-threatening clotting disorder in infants, called purpura fulminans. This causes blood clots to form in the small blood vessels throughout the body, blocking normal blood flow and potentially leading to localized necrosis.

Pathogenic variants in PROS1 are identified in approximately 43% of affected individuals.

Protein S deficiency is inherited in an autosomal dominant pattern.

While most people with protein S deficiency never develop abnormal blood clots, certain factors can increase the risk, including advanced age, surgery, trauma, inactivity, and pregnancy. Having another inherited disorder of blood clotting in addition to protein S deficiency can also influence the risk of abnormal blood clotting.

The lifetime risk for individuals with protein S deficiency of developing thrombosis is 30 times greater than that of the general population.

The prevalence of protein S deficiency is estimated at 3-13 per 10,000 individuals in the general population. Protein S deficiency is present in approximately 1%-3% of individuals presenting with venous thromboembolism.

Analysis of the PROS1 gene may be considered in individuals with the following:

  • reduced protein S activity
  • venous thromboembolism (VTE) at an unusual site (e.g., cerebral mesenteric, portal, hepatic)
  • recurrent VTE
  • idiopathic VTE (unrelated to surgery/trauma)
  • VTE under the age of 50
  • VTE during pregnancy or in the postpartum period
  • recurrent fetal loss, especially in the second or third trimesters
  • VTE while on oral contraceptives, hormone replacement, or methotrexate
  • life-threatening venous thrombosis (e.g., pulmonary embolism, cerebral vein thrombosis)
  • infants/children with purpura fulminans
  • family history of VTE in first-degree relatives
  • family history of protein S deficiency

Recommendations on when to test an individual for thrombophilias including protein S have been suggested:

  1. Baglin, T, et al. Clinical guidelines for testing for heritable thrombophilia. Br. J. Haematol. 2010; 149(2):209-20. doi: 10.1111/j.1365-2141.2009.08022.x. PMID: 20128794
  2. Borgel, D, et al. Protein S deficiency. Thromb. Haemost. 1997; 78(1):351-6. doi: 10.1016/s0899-7071(97)84577-9. PMID: 9198178
  3. Caspers, M, et al. Deficiencies of antithrombin, protein C and protein S - practical experience in genetic analysis of a large patient cohort. Thromb. Haemost. 2012; 108(2):247-57. doi: 10.1160/TH11-12-0875. PMID: 22627591
  4. Crowther, MA, Kelton, JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann. Intern. Med. 2003; 138(2):128-34. doi: 10.7326/0003-4819-138-2-200301210-00014. PMID: 12529095
  5. Dykes, AC, et al. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br. J. Haematol. 2001; 113(3):636-41. doi: 10.1046/j.1365-2141.2001.02813.x. PMID: 11380449
  6. Lijfering, WM, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009; 113(21):5314-22. doi: 10.1182/blood-2008-10-184879. PMID: 19139080
  7. Martinelli, I, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. 1998; 92(7):2353-8. PMID: 9746774
  8. Pintao, MC, et al. Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood. 2013; 122(18):3210-9. doi: 10.1182/blood-2013-04-499335. PMID: 24014240
  9. Price, VE, et al. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med. 2011; 16(6):318-22. doi: 10.1016/j.siny.2011.07.009. PMID: 21839696
  10. Reich, LM, et al. Role of the geneticist in testing and counseling for inherited thrombophilia. Genet. Med. 2003; 5(3):133-43. doi: 10.1097/01.GIM.0000067987.77803.D0. PMID: 12792420
  11. Ten, Kate, MK, et al. PROS1 analysis in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype-phenotype associations. Hum. Mutat. 2008; 29(7):939-47. doi: 10.1002/humu.20687. PMID: 18435454
  12. Varga, EA, Kujovich, JL. Management of inherited thrombophilia: guide for genetics professionals. Clin. Genet. 2012; 81(1):7-17. doi: 10.1111/j.1399-0004.2011.01746.x. PMID: 21707594
  13. ten, Kate, MK, van, der, Meer, J. Protein S deficiency: a clinical perspective. Haemophilia. 2008; 14(6):1222-8. doi: 10.1111/j.1365-2516.2008.01775.x. PMID: 18479427

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
PROS1 NM_000313.3