Submissions for variant NM_000552.5(VWF):c.4213AAG[3] (p.Lys1408del)

dbSNP: rs61750078

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Versiti Diagnostic Laboratories, Versiti, Inc	RCV001093530	SCV001250577	pathogenic	von Willebrand disease type 2M	2020-01-23	criteria provided, single submitter	clinical testing	The in-frame deletion variant VWF c.4222_4224delAAG, p.Lys1408del (p.K1408del) in exon 28 results in the deletion of amino acid lysine at codon 1408. This amino acid deletion occurs in a four lysine residue repeat in the A1 domain (Hilbert, 2000), a functional domain that binds GP1ba and collagen (Springer, 2014). Pathogenic variants in VWF are associated with autosomal dominant or autosomal recessive von Willebrand disease (VWD), characterized by quantitative or qualitative deficiencies in von Willebrand factor and resulting in prolonged bleeding. This sequence variant has been previously identified as a de novo variant in a patient reported with type 1 VWD (James, 2007), in several patients with type 2M VWD (Hilbert, 2000; Borras 2017), and has been observed in several patients with type 2M VWD in our laboratory cohort. To date, this variant has not been reported in the general population (GnomAD). Functional studies of the variant in mammalian cells demonstrated decreased secretion and lack of platelet GPIb binding in the presence of ristocetin and botrocetin (Hilbert, 2000). In summary, the collective evidence supports VWF c.4222_4224delAAG, p.Lys1408del as a pathogenic variant with regards to autosomal dominant type 2M von Willebrand disease.
Laboratory of Hematology, Radboud University Medical Center	RCV002243739	SCV002546313	pathogenic	von Willebrand disease type 2	2020-12-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271406	SCV002555823	pathogenic	Hereditary von Willebrand disease	2022-06-10	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4222_4224delAAG (p.Lys1408del) results in an in-frame deletion that is predicted to remove 1 amino acid from the von Willebrand factor, type A domain (IPR002035) of the encoded protein. The variant was absent in 251108 control chromosomes (gnomAD). c.4222_4224delAAG has been reported in the literature in multiple individuals/families affected with Von Willebrand Disease (e.g. Hilbert_2000, James_2007, Roberts_2016, Veyradier_2016, Borras_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant was deficient in both ristocetin and botrocetin-induced binding to platelets (Hilbert_2000). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance, while another ClinVar submitter (evaluation after 2014) cites it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Arcensus	RCV002466251	SCV002564566	likely pathogenic	von Willebrand disease type 1	2013-02-01	criteria provided, single submitter	clinical testing
Academic Unit of Haematology, University of Sheffield	RCV000086745	SCV000118951	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002243739	SCV002513399	uncertain significance	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724806	SCV005336128	pathogenic	VWF-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The VWF c.4222_4224delAAG variant is predicted to result in an in-frame deletion (p.Lys1408del). This variant has been reported in the heterozygous state in several individuals/families with von Willebrand disease type 2M (Borràs et al. 2017. PubMed ID: 28971901. Table S8; Reported as del AAG 4463-4465, Hilbert et al. 2000. PubMed ID: 10959688; Turan and Kadir. 2021. PubMed ID: 34889419). This variant has also been reported in the de novo state in an individual with von Willebrand disease type 1 (James et al. 2007. PubMed ID: 17190853). The functional study showed that this variant affected both ristocetin and botrocetin-induced binding to platelets (Reported as del AAG 4463-4465, Hilbert et al. 2000. PubMed ID: 10959688). This variant has conflicting classifications listed in ClinVar ranging from uncertain significance to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/100340/). This variant has not been reported in a large population database; however, the quality of this data is questionable and should be treated with caution. This variant is interpreted as pathogenic.