Submission Details

HRG was first associated with hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency in 1998 (PMID: 9414276). The spectrum of coagulation disorders currently reported in HRG-deficient patients includes transverse sinus thrombosis, dual arteriovenous fistula at sites of previous thrombosis and deep vein thrombosis. This association was made using case-level data and experimental evidence. At least 3 unique missense variants have been reported in humans in at least 3 probands in 3 publications (PMID: 9414276, 29108964, 11057869). Variants in this gene segregated with thrombosis in 3 additional family members and segregated with HRG deficiency in 8 family members. Two of the HRG variant proteins were found to be only partially secreted and haploinsufficiency is therefore proposed as a pathogenic mechanism (PMID: 9414276). It is noteworthy that multiple thrombophilia families have elevated levels of plasma HRG, as reported in several studies (Castaman et al., 1993), which seems contradictory to the phenomenon observed in HRG-deficient families. One possible explanation is that HRG mutations lead to decreased levels of plasma HRG, whereas HRG mutations negative patients have compensatory elevated plasma secondary to thromboembolism events. A role of HRG in hemostasis has been repeatedly proposed based on the observation that HRG binds several components of the coagulation and fibrinolysis cascades. Experimental evidence supporting the association with thrombophilia includes the biochemical functions of inactivating platelet thrombospondin, a strong promoter of platelet aggregation (PMID: 6690483) and inhibiting autoactivation of factor XII and factor XIIa–mediated activation of factor XI, thus modulating the intrinsic pathway of coagulation (PMID: 21304106), as confirmed in HRG-deficient plasma (PMID: 21304106). Additionally, a null mouse model has been shown to have shortened prothrombin time and tail bleeding time in the absence of HRG (PMID: 15869579), as well as accelerated carotid artery occlusion (PMID: 25691157), due to the role of HRG as a regulator of the intrinsic pathway (PMIDs: 25691157, 34474475). Administration of human HRG abrogated the effects on prothrombin time and carotid artery occlusion. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen Hemostasis Thrombosis Gene Curation Expert Panel on December 15, 2021. This gene-disease relationship was reevaluated on February 5, 2024. As a result of this reevaluation, the classification did not change.