Thrombophilia due to thrombin defect: genes and variants

Genes linked to Thrombophilia due to thrombin defect

• MTHFR: Methylenetetrahydrofolate reductase (NADPH)

  It generates 5-methyltetrahydrofolate for remethylation of homocysteine to methionine, linking folate metabolism with methyl-group supply. Severe biallelic deficiency causes homocystinuria with neurologic and thrombotic complications, while common variants produce much smaller effects on homocysteine.

  6 disease-causing and 13 uncertain variants in MTHFR are linked to Thrombophilia due to thrombin defect.

• F2: Prothrombin

  After cleavage to thrombin, it converts fibrinogen to fibrin and activates multiple additional coagulation components to amplify clot formation. Deficiency can cause bleeding, whereas the common G20210A variant raises prothrombin levels and increases venous-thrombosis risk.

  3 disease-causing and 12 uncertain variants in F2 are linked to Thrombophilia due to thrombin defect.

• F5: Coagulation factor V

  After activation, it serves as an essential cofactor for factor Xa in the prothrombinase complex and greatly accelerates thrombin generation. Deficiency can cause bleeding, whereas factor V Leiden produces activated-protein-C resistance and substantially increases venous-thrombosis risk.

  0 disease-causing and 55 uncertain variants in F5 are linked to Thrombophilia due to thrombin defect.

• F13A1: Coagulation factor XIII A chain

  After thrombin activation, it crosslinks fibrin strands and other proteins to stabilize the newly formed blood clot. Biallelic deficiency causes severe bleeding with poor wound healing and a characteristic risk of delayed bleeding and intracranial hemorrhage.

  0 disease-causing and 6 uncertain variants in F13A1 are linked to Thrombophilia due to thrombin defect.

Known disease-causing variants in Thrombophilia due to thrombin defect

Which prediction tools work for Thrombophilia due to thrombin defect

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 89 out of 100
• SIFT: 84 out of 100

Same protein, different disease

• Homocystinuria due to methylene tetrahydrofolate reductase deficiency is also caused by MTHFR variants; they fall mostly in different places as the Thrombophilia due to thrombin defect variants (43 disease-causing).
• Neural tube defects, folate-sensitive is also caused by MTHFR variants; they fall mostly in different places as the Thrombophilia due to thrombin defect variants (19 disease-causing).
• Prothrombin deficiency is also caused by F2 variants; they fall mostly in different places as the Thrombophilia due to thrombin defect variants (17 disease-causing).

Diseases related to Thrombophilia due to thrombin defect

• Ischemic stroke, also linked to F2 and F5
• Pregnancy loss, recurrent, susceptibility to, 1, also linked to F2 and F5
• Homocystinuria due to methylene tetrahydrofolate reductase deficiency, also linked to MTHFR
• Neural tube defects, folate-sensitive, also linked to MTHFR
• Prothrombin deficiency, also linked to F2
• Factor V deficiency, also linked to F5
• Factor XIII, A subunit, deficiency of, also linked to F13A1
• Schizophrenia, also linked to MTHFR
• Hereditary thrombophilia due to congenital protein C deficiency, also linked to F2
• Factor XIII deficiency, also linked to F13A1
• Thrombophilia due to activated protein C resistance, also linked to F5

Frequently asked questions

Which genes are linked to Thrombophilia due to thrombin defect?

In CATVariant, Thrombophilia due to thrombin defect is linked to 4 analyzed proteins: MTHFR (Methylenetetrahydrofolate reductase (NADPH)), F2 (Prothrombin), F5 (Coagulation factor V) and F13A1 (Coagulation factor XIII A chain).

How many genetic variants are linked to Thrombophilia due to thrombin defect?

127 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 86 are of uncertain significance or have conflicting reports.

Which uncertain variants in Thrombophilia due to thrombin defect look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Thrombophilia due to thrombin defect?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 8 disease-causing and 68 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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