Submissions for variant NM_000173.7(GP1BA):c.763A>G (p.Met255Val)

dbSNP: rs121908064

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851872	SCV000899905	likely pathogenic	Thrombocytopenia	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851873	SCV000899906	likely pathogenic	Impaired ristocetin-induced platelet aggregation	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810831	SCV002048708	pathogenic	not provided	2021-07-16	criteria provided, single submitter	clinical testing	The GP1BA c.763A>G; p.Met255Val variant (rs121908064), also known as Met239Val in alternate nomenclature, is reported in the literature in multiple individuals affected with pseudo-von Willebrand disease, also called platelet-type von Willebrand disease (Desai 2015, Giannini 2010, Kunishima 1997, Russell 1993, Takahashi 1995). This variant was observed to co-segregate with disease in several small kindreds (Russell 1993, Takahashi 1995) and was confirmed to have arisen de novo in another family (Kunishima 1997). The p.Met255Val variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 255 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.308). However, functional analyses of patient megakaryocytes with this variant exhibit increased binding to von Willebrand factor (Bury 2019). Based on available information, this variant is considered to be pathogenic. References: Bury L et al. Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. Haematologica. 2019 Jul;104(7):1473-1481. PMID: 30655369. Desai DS et al. Elderly female with a personal and family history of a bleeding disorder. Clin Chem. 2015 Jul;61(7):909-12. PMID: 26116638. Giannini S et al. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica. 2010 Jun;95(6):1021-4. PMID: 19951970. Kunishima S et al. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease. Blood Coagul Fibrinolysis. 1997 Jul;8(5):311-5. PMID: 9282797. Russell SD and Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood. 1993 Apr 1;81(7):1787-91. PMID: 8384898. Takahashi H et al. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease. Blood. 1995 Feb 1;85(3):727-33. PMID: 7833477.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000004372	SCV002500881	pathogenic	Pseudo von Willebrand disease		criteria provided, single submitter	clinical testing
OMIM	RCV000004372	SCV000024543	pathogenic	Pseudo von Willebrand disease	1993-04-01	no assertion criteria provided	literature only