Submissions for variant NM_000552.5(VWF):c.6553C>T (p.Arg2185Trp)

gnomAD frequency: 0.00003  dbSNP: rs569962285

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen	RCV004821290	SCV005442529	uncertain significance	Hereditary von Willebrand disease	2024-08-13	reviewed by expert panel	curation	NM_000552.5:c.6553C>T is a missense variant in VWF predicted to cause substitution of arginine by tryptophan at amino acid 2185. The Grpmax filtering allele frequency in gnomAD v4.1 is 0.0001538 (based on 21/91066 alleles in the South Asian population). This intermediate allele frequency is lower than the ClinGen VWD VCEP threshold (>0.01) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. At least 1 patient with this variant has been diagnosed with VWD Type 1 based on reduced quantity of VWF, with limited detail available (PMID: 28916584). A second patient was part of a VWD 2M cohort but has lab phenotypes more consistent with VWD Type 1, particularly reduced quantity of VWF:Ag and proportional decreases in VWF activity, collagen binding, and Factor VIII activity, with normal multimers (PMID: 34758185, PMID: 35747851). Although this variant has been observed in 1 patient with the p.Pro1266Leu and p.Val1279Ile variants also present (either in cis or in trans, PMID: 34758185), BP5 was not considered as neither variant has yet been classified by the ClinGen VWD VCEP. The computational predictor REVEL gives a score of 0.73, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). In summary, this variant meets the criteria to be classified as a variant of unknown significance for hereditary von Willebrand disease based on the ACMG/AMP criteria applied, as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PP3.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852182	SCV000899854	uncertain significance	Abnormality of coagulation	2019-02-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986084	SCV001134915	uncertain significance	not provided	2023-12-19	criteria provided, single submitter	clinical testing	The VWF c.6553C>T (p.Arg2185Trp) variant has been reported in the published literature in individuals with Type 2M von Willebrand disease, one of whom also carried a pathogenic VWF gene conversion variant (PMIDs: 35747851 (2022), 34758185 (2022)). In addition, this variant has been identified in individuals with low VWF levels (PMID: 28916584 (2017)) and with thrombotic/platelet disorders (PMID: 31064749 (2019)). The frequency of this variant in the general population, 0.00013 (4/30602 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Laboratory of Hematology, Radboud University Medical Center	RCV002264739	SCV002546349	uncertain significance	von Willebrand disease type 2	2020-12-10	criteria provided, single submitter	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV001029879	SCV001192670	likely pathogenic	von Willebrand disease type 1	2019-11-29	no assertion criteria provided	clinical testing