Submissions for variant NM_000552.5(VWF):c.4027A>G (p.Ile1343Val)

gnomAD frequency: 0.00016  dbSNP: rs150923481

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086724	SCV000884890	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	The VWF c.4027A>G; p.Ile1343Val variant (rs150923481) is reported in the literature in an individual with a bleeding disorder (Downes 2019), but has also been reported as part of a gene conversion between VWF and its pseudogene involving several base changes and a nonsense variant upstream (Bowman 2013, Corrales 2009). This variant is reported in ClinVar (Variation ID: 100319) and found in the general population with an overall allele frequency of 0.01% (30/282,120 alleles) in the Genome Aggregation Database. The isoleucine at codon 1343 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.453). Based on the available information, the clinical significance of the p.Ile1343Val variant is uncertain at this time. References: Bowman M et al. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost. 2013 Mar;11(3):512-20. Corrales I et al. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost. 2009 Mar;101(3):570-6. Downes K et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019 Dec 5;134(23):2082-2091.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851778	SCV000899713	uncertain significance	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV002272127	SCV002556593	uncertain significance	von Willebrand disease type 2	2020-09-23	criteria provided, single submitter	clinical testing	The VWF c.4027A>G; p.Ile1343Val variant (rs150923481) is reported in the literature as part of a gene conversion between VWF and its pseudogene involving several base changes and a nonsense variant upstream (Bowman 2013, Corrales 2009). This variant is reported in ClinVar (Variation ID: 100319) and found in the general population with an overall allele frequency of 0.01% (29/276522 alleles) in the Genome Aggregation Database. The isoleucine at codon 1343 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on the available information, the clinical significance of the p.Ile1343Val variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235041	SCV003934652	uncertain significance	not specified	2024-08-14	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4027A>G (p.Ile1343Val) results in a conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250752 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in VWF causing Von Willebrand Disease, allowing no conclusion about variant significance. c.4027A>G has been reported in the literature in individuals affected with Von Willebrand Disease, however it is often reported together with multiple other missense variants (phase not specified) and in some cases has been found as part of a gene conversion between VWF and its pseudogene (e.g. Kakela_2006, Bowman_2013, Downes_2019, Lago_2021, Christopherson_2022, Seidizadeh_2022, Baronciani_2021, Lapic_2022). 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, 16321553, 23311757, 35343054, 34828413, 34351388, 35505650, 35452508). ClinVar contains an entry for this variant (Variation ID: 100319). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086724	SCV004221529	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with type 2M (PMID: 16321553 (2006)) and type 2A (PMID:34828413 (2021)) von Willebrand Disease (VWD). This variant is one of multiple variants that occur as part of a gene conversion event between the normal VWF gene and its pseudogene, resulting in individuals with severe type 3 VWD (PMIDs: 33556167 (2021), 31532876 (2019), 23311757 (2013), 19277422 (2009), 16115133 (2005)). The frequency of this variant in the general population, 0.00024 (6/24912 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.
Academic Unit of Haematology, University of Sheffield	RCV000086724	SCV000118930	not provided	not provided		no assertion provided	not provided