The packet lists F2 (chromosome 11) as the only associated gene, with a ClinGen validity classification of DEFINITIVE. The packet records autosomal dominant inheritance, and GeneReviews describes prothrombin thrombophilia as inherited in an autosomal dominant manner. GeneReviews identifies the relevant variant as F2 20210GA, officially designated c.*97GA. The packet supplies no molecular mechanism, so none is described here.

GeneReviews states that no genotype-phenotype correlations have been identified for other F2 variants. It reports that all individuals described to date have had a parent who is heterozygous or homozygous for the F2 variant, and that prothrombin thrombophilia from a de novo pathogenic variant has not been reported. Because the variant is relatively frequent in the general population, one parent is occasionally homozygous or both parents heterozygous, and GeneReviews notes that a family history may appear negative when relatives did not develop thrombosis or the condition went unrecognized. For transmission, GeneReviews states that each child of a heterozygous individual has a 50% chance of inheriting the variant and that a homozygous individual transmits it to all offspring.

GeneReviews states that no clinical features are specific for prothrombin thrombophilia. It lists findings that raise suspicion of the diagnosis: a first unprovoked VTE before age 50 years, recurrent VTE, venous thrombosis at unusual sites such as the cerebral, mesenteric, portal, or hepatic veins, VTE during pregnancy or the puerperium, VTE associated with estrogen-containing oral contraceptives or hormone replacement therapy, and unprovoked VTE at any age with a first-degree relative who had VTE before age 50 years. Testing may be considered, per GeneReviews, with less specific findings such as a first unprovoked VTE after age 50 years or non-catheter-related idiopathic VTE or stroke in neonates and children.

GeneReviews also lists situations in which testing for the F2 20210GA variant is not considered appropriate, including general population screening, adults with VTE in the setting of major transient risk factors such as surgery or trauma, routine testing during pregnancy, prenatal or newborn testing, and routine testing of asymptomatic children.

According to GeneReviews, the diagnosis is established in a proband with a heterozygous or homozygous pathogenic F2 variant identified by molecular genetic testing, through targeted analysis or a multigene panel, with targeted analysis listed as detecting the variant in 100% of probands. Plasma prothrombin concentration in heterozygotes overlaps the normal range and is described as not reliable for diagnosis. GeneReviews names other inherited thrombophilias, including factor V Leiden and deficiencies of proteins C, S, and antithrombin, in the differential diagnosis.

The packet lists no foundational therapies, so this section follows GeneReviews management and the FDA records in the packet. The FDA records list several heparin sodium products (NDA, CDER) with ACTIVE market status, without an indication linking them to this condition. The packet also holds a record for Ceprotin, a protein C concentrate whose listed indication is congenital protein C deficiency, a different condition.

GeneReviews describes management of thrombosis as dependent on clinical circumstances. For initial VTE treatment in adults, it states that current guidelines suggest a direct oral anticoagulant (dabigatran, edoxaban, rivaroxaban, or apixaban) over warfarin because of lower bleeding risk and greater convenience, with exceptions in subgroups such as severe renal insufficiency, antiphospholipid antibody syndrome, or extremes of body weight. For individuals not given a direct oral anticoagulant, it describes warfarin together with low molecular-weight heparin or fondaparinux. Duration of oral anticoagulation is described as based on individualized assessment of recurrence and bleeding risk; heterozygosity alone is described as not an indication for long-term anticoagulation in the absence of other risk factors, and long-term anticoagulation is occasionally considered in selected individuals homozygous for 20210GA or with multiple thrombophilic disorders.

For children, GeneReviews states that treatment approaches are largely adapted from adult studies and that there is no evidence that identifying the variant influences anticoagulation intensity or duration. It also describes estrogen-containing contraception and hormone replacement therapy as agents of concern for women with prior VTE who are heterozygous and for homozygous women.

The packet contains no natural history field or explicit prognosis source, so prognosis is not certified in this packet. The GeneReviews clinical description states that clinical expression is variable, that many individuals with the F2 variant never develop thrombosis, and that some have recurrent VTE before age 30 years.

The packet records ClinicalTrials.gov trials matched to this condition through a broad venous thromboembolism term; the titles largely concern venous thrombosis in general, and a title does not establish what a study tests in relation to this condition. Examples include NCT07213778, a Phase 3 Regeneron Pharmaceuticals trial of REGN7508 versus acetylsalicylic acid for thromboprophylaxis after total knee arthroplasty (recruiting, started 2025-11-24), and NCT05701917, an Inari Medical trial of the ClotTriever System versus anticoagulation in deep vein thrombosis (recruiting, started 2023-01-06). The packet's trial summary lists drug, device, and procedural interventions and no gene therapy trials. GeneReviews points to ClinicalTrials.gov and the EU Clinical Trials Register for information on clinical studies. The packet lists no patient organizations, which reflects an empty field in the packet.