Submissions for variant NM_000552.5(VWF):c.1922C>T (p.Ala641Val)

gnomAD frequency: 0.00098  dbSNP: rs61754019

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086582	SCV000602291	uncertain significance	not provided	2023-04-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0024 (117/48744 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 1A (PMIDs: 16985174 (2007), 18230755 (2008), and 18344424 (2008)). 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, we are unable to determine the clinical significance of this variant.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851726	SCV000899579	likely pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
GeneDx	RCV000086582	SCV001785097	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in an individual with type 1 von Willebrand disease; however, this individual had normal multimers, and incomplete cosegregation of the A641V variant with von Willebrand disease in the family was reported (Goodeve et al., 2007; Castaman et al., 2008); Reported as heterozygous in a patient with coagulation disease from the published literature; however this patient also harbored a variant in the F11 gene (Downes et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27734074, 22995991, 16985174, 19506353, 18344424, 18230755, 31064749, 33556167)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313777	SCV004013083	uncertain significance	Hemorrhage		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004595919	SCV005090408	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004595919	SCV005185282	uncertain significance	not specified	2024-05-09	criteria provided, single submitter	clinical testing	Variant summary: VWF c.1922C>T (p.Ala641Val) results in a non-conservative amino acid change located in the VWF/SSPO/Zonadhesin-like, cysteine-rich domain (IPR014853) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 84122 control chromosomes. c.1922C>T has been reported in the literature in individuals affected with Von Willebrand Disease (example, Downes_2019, Goodeve_2007, Sadler_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 31064749, 16985174, 33556167). ClinVar contains an entry for this variant (Variation ID: 100196). Based on the evidence outlined above, the variant was classified as uncertain significance.
Academic Unit of Haematology, University of Sheffield	RCV000086582	SCV000118786	not provided	not provided		no assertion provided	not provided
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477864	SCV000536884	uncertain significance	von Willebrand disease type 1; von Willebrand disease type 3; von Willebrand disease type 2	2016-02-09	no assertion criteria provided	research