Submissions for variant NM_000552.5(VWF):c.5014G>A (p.Gly1672Arg)

gnomAD frequency: 0.00018  dbSNP: rs61750598

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086824	SCV001134906	uncertain significance	not provided	2024-08-19	criteria provided, single submitter	clinical testing	The VWF c.5014G>A (p.Gly1672Arg) variant has been reported in the published literature in individuals affected with von Willebrand Disease Type 2A (PMIDs: 8865541 (1996), 31249928 (2017), 31026269 (2019), and 26986123 (2016)) as well as in an individual with thrombotic microangiopathy on kidney biopsy with severe hypertension (PMID: 37103770 (2023)). The frequency of this variant in the general population, 0.0042 (16/3792 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV000086824	SCV002107212	uncertain significance	not provided	2022-02-23	criteria provided, single submitter	clinical testing	Reported with a second VWF variant, phase unknown, in unrelated patients with von Willebrand disease in published literature (Manderstedt et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8865541, 19506362, 11686104, 19453940, 32237035, 23216583, 12551832, 31026269, 31249928)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281925	SCV002570654	uncertain significance	not specified	2022-07-13	criteria provided, single submitter	clinical testing	Variant summary: VWF c.5014G>A (p.Gly1672Arg) results in a non-conservative amino acid change located in the carboxyl-terminal end of the A2 domain (Hagiwara_1996) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 247774 control chromosomes. This frequency does not allow conclusions about variant significance. c.5014G>A has been reported in the literature among individuals undergoing sequencing of the vWF gene for von Willebrand Disease (example, Hagiwara_1996, Veyradier_2016, Manderstedt_2018). In at-least one ascertained report, this variant was in cis with another reportedly known vWF gene mutation in all three families examined leading authors to speculate a common origin and occurence on the same haplotype (Manderstedt_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Academic Unit of Haematology, University of Sheffield	RCV000086824	SCV000119030	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002243745	SCV002513396	uncertain significance	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing