Submissions for variant NM_000552.5(VWF):c.974G>T (p.Cys325Phe)

gnomAD frequency: 0.00111  dbSNP: rs11837584

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002250752	SCV002521782	uncertain significance	von Willebrand disease type 3	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.038%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 3CNET). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001358270	SCV002774753	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported among a cohort of families with von Willebrand disease (PMID: 26986123 (2016)). The frequency of this variant in the general population, 0.004 (99/24962 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001358270	SCV004562045	uncertain significance	not provided	2023-10-06	criteria provided, single submitter	clinical testing	The VWF c.974G>T; p.Cys325Phe variant (rs11837584) is reported in the literature in a cohort of individuals with VWD type 1 (Veyradier 2016). This variant is also reported in ClinVar (Variation ID: 1050622). It is found in the African/African American population with an allele frequency of 0.4% (99/24962 alleles) in the Genome Aggregation Database. The cysteine at codon 325 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.896). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: 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. PMID: 26986123.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987850	SCV004803782	uncertain significance	not specified	2024-01-26	criteria provided, single submitter	clinical testing	Variant summary: VWF c.974G>T (p.Cys325Phe) results in a non-conservative amino acid change located in the Trypsin Inhibitor-like, cysteine rich domain (IPR002919) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251404 control chromosomes, predominantly at a frequency of 0.0043 within the African or African-American subpopulation in the gnomAD database. c.974G>T has been reported in the literature in individuals affected with Type 1 Von Willebrand Disease and a clinical or suspected diagnosis of Atypical hemolytic uremic syndrome, without strong evidence for causality (example, Connaughton_ 2023, Veyradier_2016). 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. The following publications have been ascertained in the context of this evaluation (PMID: 37466676, 26986123). ClinVar contains an entry for this variant (Variation ID: 1050622). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358270	SCV001553957	uncertain significance	not provided		no assertion criteria provided	clinical testing	The VWF p.Cys325Phe variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs11837584) and in control databases in 107 of 282802 chromosomes at a frequency of 0.000378 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 99 of 24962 chromosomes (freq: 0.003966), Latino in 5 of 35438 chromosomes (freq: 0.000141) and European (non-Finnish) in 3 of 129192 chromosomes (freq: 0.000023); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Cys325 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003444841	SCV004171671	uncertain significance	von Willebrand disease type 1	2023-11-24	no assertion criteria provided	clinical testing