Submissions for variant NM_000552.5(VWF):c.3320A>G (p.Tyr1107Cys)

gnomAD frequency: 0.00001  dbSNP: rs267607319

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086647	SCV001471887	uncertain significance	not provided	2020-03-11	criteria provided, single submitter	clinical testing	The VWF c.3320A>G; p.Tyr1107Cys variant (rs267607319) is reported in the literature in individuals affected with von Willebrand disease type 1, type 2, or type unspecified (Gadisseur 2009, Ott 2016, Veyradier 2016). This variant is also reported in ClinVar (Variation ID: 100254), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 1107 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Tyr1107Cys variant is uncertain at this time. References: Gadisseur A et al. Laboratory diagnosis of von Willebrand disease type 1/2E (2A subtype IIE), type 1 Vicenza and mild type 1 caused by mutations in the D3, D4, B1-B3 and C1-C2 domains of the von Willebrand factor gene. Role of von Willebrand factor multimers and the von Willebrand factor propeptide/antigen ratio. Acta Haematol. 2009;121(2-3):128-38. Ott HW et al. Identification of von Willebrand disease type 1 in a patient with Ehlers-Danlos syndrome classic type. Haemophilia. 2016 Jul;22(4):e309-11. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488384	SCV004241608	uncertain significance	not specified	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3320A>G (p.Tyr1107Cys) results in a non-conservative amino acid change located in the VWF/SSPO/Zonadhesin-like, cysteine-rich domain (IPR014853) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246782 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3320A>G has been reported in the literature in a female individual affected with Ehlers Danlos syndrome and von Willebrand disease type 1, was also mentioned as a genetic finding among a cohort of Type 2 VWD patients, without primary information for independent analysis (Veyradier_2016, Gadisseur_2009). These data do not allow any conclusion about variant significance. 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: 19506361, 27292226, 26986123). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Academic Unit of Haematology, University of Sheffield	RCV000086647	SCV000118851	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002243722	SCV002513369	uncertain significance	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing