Submissions for variant NM_000552.5(VWF):c.3437A>G (p.Tyr1146Cys)

dbSNP: rs267607326

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851956	SCV000899379	pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800314	SCV002046240	pathogenic	not specified	2020-09-25	criteria provided, single submitter	clinical testing	The variant has been reported as a relatively common variant in Type 2A vWD and some Type 1 vWD patients the published literature (PMID: 16985174 (2007), 17190853 (2007), 20351307 (2010), 22871923 (2012), 26986123 (2016), 26988807 (2016), 29388750 (2018), 29742318 (2018), 31249928 (2018), 31064749 (2019)). Functional studies showed that this variant caused defective intracellular packaging, reduced VWF secretion, and a FVIII binding defect as well as loss of large multimers and decreased proteolysis (PMID: 18230755 (2008), 20351307 (2010), 24598842 (2014), 27533707 (2016)). Therefore, the variant is classified as pathogenic.
Laboratory of Hematology, Radboud University Medical Center	RCV002264640	SCV002546275	pathogenic	von Willebrand disease type 1	2020-12-10	criteria provided, single submitter	research
Laboratory of Hematology, Radboud University Medical Center	RCV000024001	SCV002546277	pathogenic	von Willebrand disease type 2	2020-12-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000851956	SCV002548089	pathogenic	Hereditary von Willebrand disease	2022-05-25	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3437A>G (p.Tyr1146Cys) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 54460 control chromosomes. c.3437A>G has been reported in the literature in multiple individuals affected with Type I and Type II Von Willebrand Disease (example, Goodeve_2007, Castaman_2008, James_2007, Schneppenheim_2010, Manderstedt_2018, Fidalgo_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in inhibition of normal processing, string formation and platelet binding (Brehm_2014), defective intracellular packaging and markedly reduced VWF secretion. Loss of HMW Multimers. Demonstrated a novel FVIII binding defect (White-Adams_2016) and reduced expression (Schneppenheim_2010). One clinical diagnostic laboratory and the NIHR Bioresource Rare Diseases have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000024001	SCV000045292	pathogenic	von Willebrand disease type 2	2010-06-10	no assertion criteria provided	literature only
Academic Unit of Haematology, University of Sheffield	RCV000086656	SCV000118860	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000024001	SCV002513370	pathogenic	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing