ClinVar Miner

Submissions for variant NM_000552.5(VWF):c.3613C>T (p.Arg1205Cys)

gnomAD frequency: 0.00001  dbSNP: rs373787920
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002274046 SCV000602299 likely pathogenic not provided 2023-02-06 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000012 (3/251494 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with vWD Type 1 (PMIDs: 16321553 (2006) and 18449422 (2008)) and vWD of an unspecified type (PMID: 31064749 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851647 SCV000899687 likely pathogenic Hereditary von Willebrand disease 2019-02-01 criteria provided, single submitter research
GeneDx RCV002274046 SCV002559372 likely pathogenic not provided 2022-01-21 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with enhanced clearance of von Willebrand factor by macrophages (Rawley et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31064749, 19630772, 25690668, 16321553, 20230424, 18449422, 32108991, 16925796)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701576 SCV002598665 pathogenic von Willebrand disorder 2024-06-26 criteria provided, single submitter clinical testing Variant summary: VWF c.3613C>T (p.Arg1205Cys) results in a non-conservative amino acid change located in the von Willebrand factor, VWA N-terminal domain (IPR032361) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251494 control chromosomes. c.3613C>T has been reported in the literature in individuals affected with clinically diagnosed Von Willebrand Disease (example, Kakela_2006, Millar_2008 and Veyradier_2016). A different variant affecting the same codon has been classified as pathogenic by our lab (c.3614G>A, p.Arg1205His), supporting the critical relevance of codon 1205 to VWF protein function. At least one publication reports experimental evidence evaluating an impact on protein function resulting from significantly reduced survival of full-length VWf fragments within the cell (Rawley_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26986123, 16321553, 18449422, 25690668). ClinVar contains an entry for this variant (Variation ID: 439332). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV002274046 SCV004224372 likely pathogenic not provided 2022-11-23 criteria provided, single submitter clinical testing PM1, PM5, PS3

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