Submissions for variant NM_000552.5(VWF):c.3835G>A (p.Val1279Ile)

gnomAD frequency: 0.00048  dbSNP: rs61749376

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086686	SCV000589444	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a Korean patient with von Willebrand disease, but familial segregation information, in vitro functional studies, and additional clinical information were not included (Song et al., 2007).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 18094571, 33550700, 26986123, 31064749, 27148841, 33556167, 34828413, 19404524, 35505650, 27353798, 16115133, 29984440, 27785872, 28971901, 8096943)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851984	SCV000899697	uncertain significance	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000086686	SCV001148585	uncertain significance	not provided	2024-06-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086686	SCV001160656	uncertain significance	not provided	2024-10-28	criteria provided, single submitter	clinical testing	The VWF c.3835G>A; p.Val1279Ile variant (rs61749376), also known as Val516Ile, is reported in the literature in multiple individuals affected with von Willebrand disease, types I, 2M, or 3 (Eikenboom 1993, Elayaperumal 2018, James 2007, Kasatkar 2014, Sadler 2021, Veyradier 2016). This variant is frequently reported in cis to the pathogenic p.Pro1266Leu variant (Eikenboom 1993, James 2007), although other affected individuals with p.Val1279Ile have been reported to lack p.Pro1266Leu but carry other variants (Casana 2001, Elayaperumal 2018). The p.Val1279Ile variant has also been reported as part of a possible gene conversion between VWF and its pseudogene involving several base changes and a nonsense variant upstream (Ahmad 2014, Gupta 2008, Kasatkar 2014, Ornaghi 2021). The p.Val1279Ile variant is reported in ClinVar (ClinVar ID: 100288). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.26% (27/10,370 alleles) in the Genome Aggregation Database, but is considered a low confidence variant in the database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.54). However, given the limited clinical data and lack of functional data on p.Val1279Ile in isolation, its clinical significance is uncertain at this time. References: Ahmad F et al. Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease. Haemophilia. 2014 Jul;20(4):e311-7. PMID: 24712919. Casana P et al. New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand's disease. Haematologica. 2001 Apr;86(4):414-9. PMID: 11325649. Eikenboom JC et al. Recessive inheritance of von Willebrand's disease type I. Lancet. 1993 Apr 17;341(8851):982-6. PMID: 8096943. Elayaperumal S et al. Type-3 von Willebrand disease in India-Clinical spectrum and molecular profile. Haemophilia. 2018 Nov;24(6):930-940. PMID: 29984440. Gupta PK et al. Genetic defects in von Willebrand disease type 3 in Indian and Greek patients. Blood Cells Mol Dis. 2008 Sep-Oct;41(2):219-22. PMID: 18485763. James PD et al. The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. Blood. 2007 Jan 1;109(1):145-54. PMID: 17190853. Kasatkar P et al. Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients. PLoS One. 2014 Mar 27;9(3):e92575. PMID: 24675615. Ornaghi AP et al. Variants p.Pro2063Ser and p.Arg324Ter co-segregate in type 3 von Willebrand disease patients from Southern Brazil. Haemophilia. 2021 Mar;27(2):e204-e213. PMID: 33550700. 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. Veyradier A et al. A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. Medicine (Baltimore). 2016 Mar;95(11):e3038. PMID: 26986123.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002222388	SCV002500929	uncertain significance	von Willebrand disease type 1		criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280868	SCV002569262	uncertain significance	von Willebrand disease type 2		criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313778	SCV004013117	uncertain significance	Thrombocytopenia		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086686	SCV004221520	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	The VWF c.3835G>A (p.Val1279Ile) variant has been reported in the published literature as homozygous and as compound heterozygous with another VWF pathogenic variant in individuals affected with types 1, 2B, 2M, and 3 von Willebrand disease (VWD) (PMIDs: 8134377 (1994), 11325649 (2001), 16115133 (2005), 18315546 (2008), 18485763 (2008), 19453940 (2010), 24675615 (2014), 26986123 (2016), 29984440 (2018), and 34828413 (2021)), as well as heterozygous in individuals affected with type 1 VWD (PMID: 18094571 (2007) and 37168293 (2023)). When seen with the VWF c.3797C>T (p.Pro1266Leu) pathogenic variant, this variant has been detected in the same copy of the VWF gene (in cis) in many individuals affected with Type 1, Type 2M, Type 2B, and Type 3 vWD (PMID: 24675615 (2014), 24712919 (2014), 17190853 (2007), and 8134377 (1991)). Both variants can be detected on the same chromosome as a result of a gene conversion event between the VWF gene and its pseudogene (PMID: 18805962 (2009) and 18315546 (2008)).The frequency of this variant in the general population, 0.0026 (27/10370 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987361	SCV004804040	uncertain significance	not specified	2024-01-31	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3835G>A (p.Val1279Ile) results in a conservative amino acid change located in the von Willebrand factor, type A (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 0.00038 in 1612942 control chromosomes in the gnomAD database (v4.0.0), including 1 homozygotes. c.3835G>A has been reported in the literature in many individuals affected with Von Willebrand Disease but also frequently reported in cis with a pathogenic variant and observed to co-occur with other pathogenic variants(e.g. Eikenboom_1993, Kasatkar_2014, Kakela_2006, James_2007) . These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (VWF c.3797C>T, p.Pro1266Leu; VWF c.3931C>T, p.Q1311X), providing supporting evidence for a benign role. 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: 8096943, 17190853, 16321553, 24675615). ClinVar contains an entry for this variant (Variation ID: 100288). Based on the evidence outlined above, the variant was classified as uncertain significance.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV002222388	SCV005397317	uncertain significance	von Willebrand disease type 1	2023-05-19	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at coding nucleotide 3835 of the VWF gene that results in a valine to phenylalanine amino acid change at residue 1279 of the VWF protein. The Val1279 residue falls in the A1 domain which plays a critical role in the formation of clots (PMID: 26213126). This is a previously reported variant (ClinVar) that has been observed in both the homozygous and compound heterozygous state in individuals with von Willebrand disease (PMID: 31532876, 35505650, 29984440, 25689060, 34828413, 27353798, 35307943, 16115133). This variant is believed to be the product of a gene conversion event involving a pseudogene in several affected individuals (PMID: 16115133, 17846636). This variant is present in 83 of 282,236 alleles (0.03%) in the gnomAD control population dataset. Multiple bioinformatic tools predict that this valine to phenylalanine amino acid change would be damaging, and the valine residue at this position is strongly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM1, PP2, PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV000086686	SCV005408232	uncertain significance	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Academic Unit of Haematology, University of Sheffield	RCV000086686	SCV000118890	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000851984	SCV002507233	not provided	Hereditary von Willebrand disease		no assertion provided	literature only