Submissions for variant NM_000552.5(VWF):c.2435del (p.Pro812fs)

dbSNP: rs62643632

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000086611	SCV000855028	pathogenic	not provided	2018-04-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086611	SCV000888684	pathogenic	not provided	2023-03-09	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the VWF mRNA and causes the premature termination of VWF protein synthesis. The frequency of this variant in the general population, 0.00054 (14/26126 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been described as a common mutation in the Swedish and Finnish populations (PMIDs: 1302613 (1992), 23834637 (2013)), reported in heterozygous patients with vWD type I (PMIDs: 16985174 (2007), 17190853 (2007)), and in homozygous or compound heterozygous patients with vWD type III (PMIDs: 23834637 (2013), 29427305 (2018), 35343054 (2022)). Based on the available information, this variant is classified as pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851752	SCV000899623	pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852083	SCV000899624	pathogenic	Abnormal bleeding	2019-02-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000086611	SCV002544997	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	VWF: PVS1, PM2
Laboratory of Hematology, Radboud University Medical Center	RCV002264635	SCV002546261	pathogenic	von Willebrand disease type 1	2020-12-10	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV002476902	SCV002799677	pathogenic	von Willebrand disease type 1; von Willebrand disease type 3; von Willebrand disease type 2	2022-03-08	criteria provided, single submitter	clinical testing
Institute of Immunology and Genetics Kaiserslautern	RCV002264635	SCV004803198	pathogenic	von Willebrand disease type 1	2024-03-09	criteria provided, single submitter	clinical testing	ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state
Institute of Human Genetics, University of Leipzig Medical Center	RCV002264635	SCV005368487	pathogenic	von Willebrand disease type 1	2023-09-25	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PS3_MOD
Institute of Human Genetics, University of Leipzig Medical Center	RCV005000978	SCV005627517	pathogenic	von Willebrand disease type 2	2024-12-11	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3,PM2_SUP; Identified as compund heterozygous with NM_000552.5:c.2561G>A
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086611	SCV005878246	pathogenic	not provided	2024-07-22	criteria provided, single submitter	clinical testing	The VWF c.2435del; p.Pro812Argfs*31 variant (rs62643632; ClinVar Variation ID: 303), is the index variant for von Willebrand disease (VWD) associated with VWD type 3, and is considered a founder variant in Baltic populations (Jokela 2013, Zhang 1993). This variant causes a frameshift by deleting a single nucleotide, and a functional study has shown no protein expression from the affected allele, suggesting the mRNA is subject to nonsense-mediated decay (Flood 2012). Based on available information, this variant is considered to be pathogenic. REFERENCES: Flood VH et al. Critical von Willebrand factor A1 domain residues influence type VI collagen binding. J Thromb Haemost. 2012 Jul;10(7):1417-24. PMID: 22507569. Jokela V et al. Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations. Haemophilia. 2013 Nov;19(6):e344-8. PMID: 23834637. Zhang ZP et al. Mutations of von Willebrand factor gene in families with von Willebrand disease in the Aland Islands. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7937-40. PMID: 8367445.
OMIM	RCV000000330	SCV000020474	pathogenic	von Willebrand disease type 3	1993-12-20	no assertion criteria provided	literature only
Academic Unit of Haematology, University of Sheffield	RCV000086611	SCV000118815	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000000330	SCV001572662	pathogenic	von Willebrand disease type 3	2021-04-12	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000086611	SCV001978298	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000086611	SCV001980128	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000851752	SCV002507238	not provided	Hereditary von Willebrand disease		no assertion provided	literature only