Submissions for variant NM_000552.5(VWF):c.3101_3103del (p.Thr1034del)

dbSNP: rs368366214

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV001787121	SCV001138632	uncertain significance	von Willebrand disease type 3	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003317406	SCV001469941	likely benign	not specified	2024-02-13	criteria provided, single submitter	clinical testing	The VWF c.3101_3103del (p.Thr1034del) variant has been reported in the published literature in an individual with venous thromboembolism (PMID: 31352677 (2019)). In addition, this variant has been reported in reportedly healthy individuals (PMID: 34662354 (2021)) and in individuals affected with type 2M VWD (PMID: 22197721 (2012), 16321553 (2006)), and type 3 (PMID: 37845247 (2023)). The frequency of this variant in the general population, 0.015 (380/24964 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001284259	SCV003799939	uncertain significance	not provided	2024-11-27	criteria provided, single submitter	clinical testing	The VWF c.3101_3103del; p.Thr1034del variant (rs368366214, ClinVar Variation ID: 802812) is reported in the literature in individuals affected with von Willebrand disease (VWD), but also in healthy controls (Baronciani 2021, Bellissimo 2012, Kakela 2006, Pagliari 2021, Sadler 2021). This variant has been observed in the homozygous or compound heterozygous state in several individuals with type 3 VWD (Baronciani 2021), and in one heterozygous individual with VWD type 2M (Kakela 2006). Additionally, this variant was found in one individual with VWD type 3 that carried two nonsense variants that likely explain the observed phenotype (Marchi 2024). This variant is found in the African population with an allele frequency of 1.5% (380/24964 alleles, including three homozygotes) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein expressed in HEK293 cells demonstrate loss of high molecular weight markers (Marchi 2024). This variant deletes a single threonine residue, leaving the rest of the protein in-frame. Due to conflicting information, the clinical significance of the p.Thr1034del variant is uncertain at this time. References: Baronciani L et al. Genotypes of European and Iranian patients with type 3 von Willebrand disease enrolled in 3WINTERS-IPS. Blood Adv. 2021 Aug 10;5(15):2987-3001. PMID: 34351388. Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Kakela JK et al. Genetic mutations in von Willebrand disease identified by DHPLC and DNA sequence analysis. Mol Genet Metab. 2006 Mar;87(3):262-71. PMID: 16321553. Marchi R et al. The search for the underlying mutations causing VWD in 13 Venezuelan families. Thromb Res. 2024 Mar;235:88-91. PMID: 38308883. Pagliari MT et al. Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis. PLoS One. 2021 Oct 18;16(10):e0258675. PMID: 34662354. Sadler B et al. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood. 2021 Jun 10;137(23):3277-3283. PMID: 33556167.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV001787121	SCV004013102	uncertain significance	von Willebrand disease type 3		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317406	SCV004020737	uncertain significance	not specified	2024-03-05	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3101_3103delCCA (p.Thr1034del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.0012 in 251670 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. c.3101_3103delCCA has been reported in the literature in individuals affected with bleeding disorders including Von Willebrand Disease as well as unaffected controls (Baz_2021, Bellissimo_2012, Kakela_2006, Manderstedt_2019, Sadler_2021). These reports 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: 16321553, 22197721, 34272389, 33556167, 31352677). ClinVar contains an entry for this variant (Variation ID: 802812). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001284259	SCV004132419	benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	VWF: BS1, BS2
Mayo Clinic Laboratories, Mayo Clinic	RCV001284259	SCV004226291	uncertain significance	not provided	2022-03-03	criteria provided, single submitter	clinical testing	BS1, BS2, PM4
Breakthrough Genomics, Breakthrough Genomics	RCV001284259	SCV005191633	uncertain significance	not provided		criteria provided, single submitter	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV001787121	SCV001572672	benign	von Willebrand disease type 3	2021-04-12	no assertion criteria provided	clinical testing