THBD

Inheritance Pattern: AD

Disease ID:MONDO:0013044

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0013775

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016244

Submitter: ClinGen

THBD was first reported in relation to autosomal dominant atypical hemolytic uremic syndrome (aHUS) in 2009 (Delvaeye et al., PMID: 19625716). Genetic variants in THBD, which encodes thrombomodulin, have been reported to cause aHUS (PMID: 19625716) however, analysis of large aHUS cohorts (PMIDs: 23307876, 37369098, 37567446) and enrichment analysis (PMIDs: 29500241, 30377230) have failed to reproduce these findings. Therefore, none of the genetic variants in THBD identified in patients with aHUS were included in this curation for scoring. Furthermore, the experimental evidence available (PMID: 19625716) has been excluded in light of the evidence disputing this gene-disease relationship. In summary, the evidence supporting the relationship between THBD and autosomal dominant aHUS has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role THBD plays in this disease. This classification was approved by the ClinGen Complement-Mediated Kidney Diseases GCEP on the meeting date May 15, 2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0013044

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0013775

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0013775

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0013775

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013775

Submitter: ClinGen

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.