Submissions for variant NM_000552.5(VWF):c.817C>T (p.Arg273Trp)

gnomAD frequency: 0.00004  dbSNP: rs61753997

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003313936	SCV004013965	pathogenic	von Willebrand disease type 1	2022-10-17	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398701	SCV004122246	pathogenic	Hereditary von Willebrand disease	2023-10-27	criteria provided, single submitter	clinical testing	Variant summary: VWF c.817C>T (p.Arg273Trp) results in a non-conservative amino acid change located in the VWF/SSPO/Zonadhesin-like, cysteine-rich domain (IPR014853) 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 2.8e-05 in 251078 control chromosomes (gnomAD). c.817C>T has been reported in the literature in multiple individuals affected with Von Willebrand Disease (Allen_2000, Hampshire_2013,- Ornaghi_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant causes severely reduced VWF secretion and impaired formation of high-molecular-weight multimers (Allen_2000). The following publications have been ascertained in the context of this evaluation (PMID: 10887119, 23702511, 33550700). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000086907	SCV005414058	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1_supporting, PM3_strong, PS3
Academic Unit of Haematology, University of Sheffield	RCV000086907	SCV000119113	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004739360	SCV005361217	pathogenic	VWF-related disorder	2023-12-07	no assertion criteria provided	clinical testing	The VWF c.817C>T variant is predicted to result in the amino acid substitution p.Arg273Trp. This variant has been reported in the homozygous or compound heterozygous states in individuals with Von Willebrand Disease Types 1, 2, and 3 (Allen et al. 2000. PubMed ID: 10887119; Hampshire et al. 2013. PubMed ID: 23702511; Ornaghi et al. 2021. PubMed ID: 33550700). Heterozygous carriers of p.Arg273Trp were apparently unaffected in one report suggesting that the p.Arg273Trp substitution may need to be paired with a second variant VWF allele or a particular genetic background to be disease causing (Hampshire et al. 2013. PubMed ID: 23702511). Functional studies indicate the p.Arg273Trp substitution causes impaired secretion of VWF protein and failure of VWF protein to form high molecular weight multimers (Allen et al. 2000. PubMed ID: 10887119; Allen et al. 2001. PubMed ID: 11162537). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.