Submissions for variant NM_000552.5(VWF):c.4825G>A (p.Gly1609Arg)

dbSNP: rs61750580

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086804	SCV001988468	uncertain significance	not provided	2019-04-22	criteria provided, single submitter	clinical testing	Identified as heterozgyous in multiple individuals, including a family with multiple affected individuals, with von Willebrand disease type 2A in the literature (Donner et al., 1993; Choi et al., 2012); Published functional studies demonstrate a damaging effect resulting in increased proteolysis (Hassenpflug et al., 2006); This variant is associated with the following publications: (PMID: 8348943, 16322474, 22371917)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387760	SCV004099770	pathogenic	Hereditary von Willebrand disease	2023-09-12	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4825G>A (p.Gly1609Arg) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251200 control chromosomes. c.4825G>A has been reported in the literature in multiple individuals affected with Von Willebrand Disease (e.g. Donner_1993, Choi_2012, Sadler_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that it resulted in substantially increased ADAMTS13-dependent proteolysis of VWF (Hassenpflug_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16322474, 22371917, 8348943, 33556167). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Academic Unit of Haematology, University of Sheffield	RCV000086804	SCV000119010	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002243743	SCV002513363	likely pathogenic	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing