Submission Details

THBD was first reported in relation to autosomal dominant thrombomodulin-related bleeding disorder in 2014 [PMID: 25049278]. Two different truncating variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in five probands in five publications [PMID: 25049278, 25564403, 27436851, 28267383, 33190022]. This gene-disease relationship is supported by its protein interactions with Thrombin, which regulates anticoagulant pathway [PMID: 8663147], biochemical function that THBD protein forms a 1:1 complex with the coagulation factor thrombin and alters thrombin's specificity toward several substrates, ultimately acting as an antithrombotic factor [PMID:22036808], Expression studies that Thrombomodulin is found in most human endothelium including that of arteries, veins, capillaries, and lymphatics. This localization well serves its function as a cofactor for protein C activation [PMID: 2991298], Expression studies that high soluble THBD protein in plasma in the patients [PMID: 25564403], functional alteration in patient cells showing reduced tissue factor-induced thrombin generation and significantly delayed plasma clots lysis, and Model Systems using cell culture that addition of soluble TM to control plasma caused dose-dependent reductions in ETP and peak thrombin, which were similar to the patients [PMID: 27436851]. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen Hemostasis Thrombosis Gene Curation Expert Panel on Dec 10, 2021. This gene-disease relationship was reevaluated on November 06, 2023. As a result of this reevaluation, the classification did not change.