THBD was first reported in relation to autosomal recessive thrombomodulin-related bleeding disorder in 2020 [PMID: 32556284]. Two different homozygous missense 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 two probands in two publications [PMID: 32556284, 34474479]. 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], functional alteration in the COS-1 cells showing that missense variant C265S variant reduced THBD expression on the cell membrane, and also PC and TAFI activation activities were decreased as well [PMID: 34474479]. Two rescue studies in the two different homozygous missense patients showed that recombinant human soluble TM(rhTM) could improve patients’ coagulation status significantly, however, the rhTM-variant couldn’t rescue the phenotypes[PMID: 32556284, 34474479]. In summary, there is moderate evidence to support this gene-disease relationship. However, there are only two independent variant families reported, the final classification is downgraded from moderate to limited. 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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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