Submissions for variant NM_000552.5(VWF):c.3108+5G>A

gnomAD frequency: 0.00001  dbSNP: rs61748495

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852109	SCV000899667	uncertain significance	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
GeneDx	RCV000086638	SCV001825525	likely pathogenic	not provided	2021-02-08	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31064749, 17080221, 29562472, 12737944, 18510569, 23520336, 26986123)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000852109	SCV002511556	pathogenic	Hereditary von Willebrand disease	2022-04-15	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3108+5G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 5' splicing donor site, while three predict the variant weakens a 5' donor site. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing, by demonstrating skipping of exon 23 from patient derived RNA (Cumming_2006). The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes (gnomAD). The variant, c.3108+5G>A, has been reported in the literature in homozygous and compound heterozygous state in individuals affected with Von Willebrand Disease (VWD) Type 3 (Baronciani_2003, Cumming_2006). The variant was also reported in heterozygous state in several individuals with a milder phenotype, i.e. VWD type 1 (see e.g. Cumming_2006, Flood_2013, Roberts_2016, Downes_2019), and in a large family the variant segregated with the phenotype (Cumming_2006). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, one laboratory classified the variant as likely pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280867	SCV002569256	uncertain significance	von Willebrand disease type 1		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086638	SCV004221505	pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251178 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been identified in one compound heterozygote and one homozygote, both with type 3 VWD (PMID: 17080221 (2006), 12737944 (2003)). Additionally, the variant has also been reported to segregate with disease in one affected family (PMID: 17080221 (2006)). Splicing analysis has shown that the variant results in a skipping of exon 23, however the percent of affected transcribed RNAs is unknown (PMID: 17080221 (2006)). Additional analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper VWF mRNA splicing. Based on the available information, this variant is classified as pathogenic.
Academic Unit of Haematology, University of Sheffield	RCV000086638	SCV000118842	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002243721	SCV002513371	likely pathogenic	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing