ClinVar Miner

Submissions for variant NM_000552.5(VWF):c.3917G>A (p.Arg1306Gln)

gnomAD frequency: 0.00001  dbSNP: rs61749385
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000086700 SCV000602303 pathogenic not provided 2022-05-04 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with type 2B von Willebrand disease (VWD) (PMIDs: 9198195 (1997), 9858249 (1998), 17598021 (2007), 28971901 (2017)). This variant is located in the glycoprotein Ib (GPIb)-binding site of VWF, and has been shown to allow normal VWF multimerization but cause abnormal increased affinity of plasma VWF for platelets (PMIDs: 9108394 (1997), 9858249 (1998), 20200350 (2010)). Based on the available information, this variant is classified as pathogenic.
Academic Unit of Haematology, University of Sheffield RCV000086700 SCV000118904 not provided not provided no assertion provided not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico RCV002243729 SCV002513382 pathogenic von Willebrand disease type 2 2022-04-26 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004739357 SCV005343663 pathogenic VWF-related disorder 2024-03-18 no assertion criteria provided clinical testing The VWF c.3917G>A variant is predicted to result in the amino acid substitution p.Arg1306Gln. This variant (aka p.Arg543Gln) has been reported in multiple individuals with von Willebrand disease (VWD) type 2B (Hilbert et al. 1998. PubMed ID: 9858249; Szántó et al. 2007. PubMed ID: 17598021; Borràs et al. 2017. PubMed ID: 28971901. Table S7; Sadler et al. 2021. PubMed ID: 33556167. Table S3). In vitro and in vivo functional studies have demonstrated that this variant increases VWF binding affinity toward platelet-bound glycoprotein 1b-alpha (GP1Ba), leading to platelet aggregation (Yago et al. 2008. PubMed ID: 18725999; Rayes et al. 2010. PubMed ID: 20200350; Tischer et al. 2014. PubMed ID: 25185554). Additional studies using an in vivo mouse model found that this variant also increases VWF binding affinity toward macrophage-bound LRP1, leading to increased clearance of mutant VWF from circulation (Wohner et al. 2015. PubMed ID: 25728415). This variant has not been reported in a large population database, indicating this variant is rare. Of note, a different missense variant at the same amino acid position (p.Arg1306Trp) is one of the most commonly reported disease-causing variants in patients with VWD type 2B (for example, see Ozeki et al. 2010. PubMed ID: 19740526; Borràs et al. 2017. PubMed ID: 28971901; Sadler et al. 2021. PubMed ID: 33556167). Taken together, the p.Arg1306Gln variant is interpreted as pathogenic.

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