Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory of Hematology, |
RCV002264667 | SCV002546246 | likely pathogenic | von Willebrand disease type 1 | 2020-12-10 | criteria provided, single submitter | research | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003478999 | SCV004223093 | uncertain significance | not specified | 2023-11-03 | criteria provided, single submitter | clinical testing | Variant summary: VWF c.55G>A (p.Gly19Arg) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3 acceptor site. Four predict the variant weakens a canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 251460 control chromosomes (gnomAD). c.55G>A has been reported in the literature in individuals affected with Von Willebrand Disease (Goodeve_2006, Hashemi Soteh_2007, Ahmad_2014, Borras_2017). These reports do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. At least one co-occurrence with another pathogenic variant has been reported (VWF c.8159delA, p.Glu2720Glyfs*24), providing supporting evidence for a benign role. At least two publications report experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Eikenboom_2009, Eikenboom_2013). The following publications have been ascertained in the context of this evaluation (PMID: 24712919, 28971901, 19566550, 23349392, 16985174, 21632843, 17488667). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Neuberg Centre For Genomic Medicine, |
RCV004771461 | SCV005382327 | uncertain significance | von Willebrand disease type 3 | 2023-05-20 | criteria provided, single submitter | clinical testing | The observed missense c.55G>A(p.Gly19Arg) variant in VWF gene has been reported previously in heterozygous / homozygous / compound heterozygous state in individual(s) affected with type 3 von Willebrand disease in a cohort of Indian patients (Ahmad et al., 2013) and type 1 von Willebrand disease (Hampshire DJ, Goodeve AC., 2011). This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid Gly at position 19 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly19Arg in VWF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The p.Gly19Arg mutation previously identified in type 1 VWD also fails to influence VWF expression in vitro but is predicted in silico to influence splicing of exon 2 (Hampshire DJ, Goodeve AC., 2011). For these reasons, this variant has been classified as Uncertain Significance. |
| Academic Unit of Haematology, |
RCV000086844 | SCV000119050 | not provided | not provided | no assertion provided | not provided |