Submissions for variant NM_000552.5(VWF):c.5278G>A (p.Val1760Ile)

gnomAD frequency: 0.00094  dbSNP: rs61750604

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852150	SCV000899790	likely pathogenic	Abnormality of coagulation	2019-02-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000086832	SCV001148576	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	VWF: BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001933	SCV001159702	uncertain significance	not specified	2019-06-27	criteria provided, single submitter	clinical testing	The VWF c.5278G>A; p.Val1760Ile variant (rs61750604) is reported in the literature in several individuals and families affected with von Willebrand disease type 1, although its clinical significance was not determined (Borras 2017, James 2007, Johansson 2011). This variant is found in the non-Finnish European population with an overall allele frequency of 0.14% (176/129096 alleles, including one homozygote) in the Genome Aggregation Database. The valine at codon 1760 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Val1760Ile variant is uncertain at this time. References: Borras N et al. Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients. Haematologica. 2017 Dec;102(12):2005-2014. 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. Johansson AM et al. Variation in the VWF gene in Swedish patients with type 1 von Willebrand Disease. Ann Hum Genet. 2011 Jul;75(4):447-55.
GeneDx	RCV000086832	SCV001793232	uncertain significance	not provided	2023-05-02	criteria provided, single submitter	clinical testing	Has been reported previously in individuals with unspecified coagulation disorder and/or clinical diagnoses of von Willebrand disease; in some individuals, a second variant in the VWF gene was identified, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (James et al., 2007; van Meegeren et al., 2015; Borrs et al. 2017; Downes et al., 2019, Gindele et al., 2021, Sadler et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30722078, 26207643, 31064749, 21534937, 28971901, 23216583, 17190853, 33556167, 31249928, 19506353, 29924855, 33477601, 33807613)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001001933	SCV002046255	uncertain significance	not specified	2020-10-09	criteria provided, single submitter	clinical testing
Mendelics	RCV001001933	SCV002516162	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001001933	SCV004813680	uncertain significance	not specified	2025-01-06	criteria provided, single submitter	clinical testing	Variant summary: VWF c.5278G>A (p.Val1760Ile) 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 0.00076 in 251378 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. 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.5278G>A has been reported in the literature in individuals affected with Von Willebrand Disease without strong evidence of causality (e.g. James_2007, Meegeren_2015, Borras_2017, Downes_2019, Vangenechten_2019, Gindele_2021, Preisler_2021, 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: 28971901, 37466676, 31064749, 33807613, 17190853, 26207643, 33477601, 33556167, 30722078). ClinVar contains an entry for this variant (Variation ID: 100422). Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786367	SCV005399933	uncertain significance	Hereditary von Willebrand disease	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0103- Loss of function is known mechanism of disease in this gene and is associated with von Willebrand disease, while dominant negative has been stipulated for a single missense variant (OMIM, PMID: 11698279). (I) 0108 - This gene is associated with both recessive and dominant disease. von Willebrand disease can be both dominantly and recessively inherited, and is categorised into 6 different types: 1 (MIM#193400), 2A, 2B, 2M, 2N (MIM#613554) and 3 (MIM#277480). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 212 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated VWA_3 domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been described as a variant of uncertain significance by diagnostic laboratories and has been reported in patients with autosomal dominant Type1 von Willebrand disease (MIM#193400) and a single report of a patient with autosomal recessive Type 2N von Willebrand disease (MIM#613554). However, in the reports of Type 1 patients, this variant is one of two variants detected therefore making its pathogenicity tenous (ClinVar, PMID: 17190853, 28971901, 30722078, 26207643). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000086832	SCV005408224	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	BP4, PS4_moderate
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359028	SCV005921259	uncertain significance	von Willebrand disease type 1; von Willebrand disease type 3	2021-09-15	criteria provided, single submitter	research
Academic Unit of Haematology, University of Sheffield	RCV000086832	SCV000119038	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000086832	SCV001932286	likely benign	not provided		flagged submission	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000086832	SCV001955795	likely benign	not provided		flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549532	SCV004116523	uncertain significance	VWF-related disorder	2024-04-25	no assertion criteria provided	clinical testing	The VWF c.5278G>A variant is predicted to result in the amino acid substitution p.Val1760Ile. This variant has been reported in individuals with Von Willebrand disease, yet some of these individuals carried a second VWF variant with unknown phase, and no functional or family segregation studies clearly support its pathogenicity (James et al. 2007. PubMed ID: 17190853; Downes et al. 2019. PubMed ID: 31064749; Sadler et al. 2021. PubMed ID: 33556167). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.