Submissions for variant NM_000552.5(VWF):c.7493C>A (p.Ala2498Asp)

gnomAD frequency: 0.00004  dbSNP: rs369669154

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851866	SCV000899899	likely pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
Laboratory of Hematology, Radboud University Medical Center	RCV002264735	SCV002546250	uncertain significance	von Willebrand disease type 1	2020-12-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226384	SCV003922744	uncertain significance	not specified	2023-03-23	criteria provided, single submitter	clinical testing	Variant summary: VWF c.7493C>A (p.Ala2498Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251332 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7493C>A has been reported in the literature 1. among individuals undergoing multigene panel testing for von Willebrand disease, 2. with an uncertain contribution to patient phenotype in settings of broadly defined Thrombo Genomics panel in an individual with unspecified clinical characteristics where it co-occurred with other putative likely pathogenic variants in the VWF gene and 3. as part of the Saudi Human Genome Project in an unspecified clinical cohort (example, Borras_2017, Baz_2021, Downes_2019). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001796780	SCV002037449	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001796780	SCV002037987	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549842	SCV004725329	uncertain significance	VWF-related disorder	2023-12-21	no assertion criteria provided	clinical testing	The VWF c.7493C>A variant is predicted to result in the amino acid substitution p.Ala2498Asp. This variant has been reported in some cohort studies of bleeding disorders (Borràs et al. 2017. PubMed ID: 28971901. Table S10; Downes et al. 2019. PubMed ID: 31064749. Table S3 - SNV and INDEL list; Baz et al. 2021. PubMed ID: 34272389. Table S3). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.