Submissions for variant NM_000552.5(VWF):c.2278C>T (p.Arg760Cys)

gnomAD frequency: 0.00001  dbSNP: rs61748466

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086594	SCV002046705	uncertain significance	not provided	2021-03-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086594	SCV002049557	likely pathogenic	not provided	2021-02-20	criteria provided, single submitter	clinical testing	The VWF c.2278C>T; p.Arg760Cys variant (rs61748466) is reported in the literature in multiple individuals affected with von Willebrand disease (VWD) type 2N (Casonato 2003, Casonato 2017, Koessler 2011, Veyradier 2011). Functional analyses demonstrate that this variant inhibits the cleavage of the VWF propeptide leading to the persistence of the VWF propeptide, a condition that impairs the FVIII binding capacity of VWF (Casonato 2003). This variant is also reported in ClinVar (Variation ID: 100208). This variant is found in the general population with an overall allele frequency of 0.0018% (5/282708 alleles) in the Genome Aggregation Database. The arginine at codon 760 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.219). Based on available information, this variant is considered to be likely pathogenic. References: Casonato A et al. An Arg760Cys mutation in the consensus sequence of the von Willebrand factor propeptide cleavage site is responsible for a new von Willebrand disease variant. Blood. 2003 Jan 1;101(1):151-6. Casonato A et al. Type 2N von Willebrand disease: Characterization and diagnostic difficulties. Haemophilia. 2018 Jan;24(1):134-140. Koessler J et al. Von Willebrand disease caused by compound heterozygosity for p.r854q and p.r760c: diagnostic and therapeutic implications. Haemophilia. 2011 Jan;17(1):e240-2. Veyradier A et al. Compound heterozygosity or heterozygosity with two mutations in cis on the same allele? A rebuttal to the letter to the Editors: Koessler et al. Von Willebrand disease caused by compound heterozygosity for p.R854Q and p.R760C: diagnostic and therapeutic implications. Haemophilia 2011; 17: e240-2. Haemophilia. 2011 Sep;17(5):e832-3.
Baylor Genetics	RCV003147338	SCV003835265	likely pathogenic	von Willebrand disease type 2	2022-06-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003992184	SCV004809827	uncertain significance	von Willebrand disease type 1	2024-04-04	criteria provided, single submitter	clinical testing
Academic Unit of Haematology, University of Sheffield	RCV000086594	SCV000118798	not provided	not provided		no assertion provided	not provided