Submissions for variant NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)

dbSNP: rs61750584

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000778377	SCV000899346	pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000778377	SCV000914596	pathogenic	Hereditary von Willebrand disease	2018-10-22	criteria provided, single submitter	clinical testing	The VWD c.4883T>C (p.Ile1628Thr) missense variant has been reported in at least four studies in which it is found in at least 28 individuals with different subtypes of von Willebrand disease (VWD) (Iannuzzi et al. 1991; Melo-Nava et al. 2007; Woods et al. 2011, Ahmad et al. 2014). In one study the p.Ile1628Thr variant was found in a heterozygous state in 18 individuals affected with type 2A VWD and was shown to segregate with disease across three generations, where the authors note that all affected family members were heterozygous for the variant, while none of the unaffected members carried the variant, however only exon 28 of the VWF gene was sequenced in this study (Iannuzzi et al. 1991). In a second study, the variant was found in a heterozygous state in five individuals, all with type 2A VWD, one with mild bleeding severity, three with moderate bleeding severity and one with severe bleeding severity (Melo-Nava et al. 2007). Woods et al. (2011) reported one individual, who was heterozygous for p.Ile1628Thr variant and affected with both type 1 and type 2M VWD, who carried an additional heterozygous missense variant inherited from his mother who was affected with type VWD. The father and sister were affected with type 2M VWD and heterozygous for the p.Ile1628Thr variant. Two further individuals with type 2A VWD and heterozygous for the p.Ile1628Thr variant were also reported. Both mothers and one sister also carried the variant, but their affected status was not clear (Ahmed et al. 2014). The p.Ile1628Thr variant was absent from 334 control alleles and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database, in a region with good sequence coverage and hence is presumed to be rare. Functional studies demonstrated that the recombinant variant protein had little or no effect on the ADAMTS13-dependent proteolysis of VWF when compared to wild type (Hassenpflug et al. 2006; Zanardelli et al. 2006). Structural studies showed that the variant destabilized the native folded state of the protein and lowered the in silico tensile force which is important in the first event of the unfolding pathway (Interlandi et al. 2012). Based on the collective evidence, the p.Ile1628Thr variant is classified as pathogenic for von Willebrand disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Versiti Diagnostic Laboratories, Versiti, Inc	RCV000000308	SCV001250578	pathogenic	Von Willebrand disease type 2A	2019-01-21	criteria provided, single submitter	clinical testing	The missense variant VWF c.4883T>C, p.Ile1628Thr (p.I1628T) in exon 28 changes amino acid isoleucine at codon 1628 to threonine. The isoleucine at this residue is highly conserved among species. This amino acid change occurs in the A2 domain, a functional domain that is cleaved by ADAMTS13 (Springer, 2014). This sequence variant has been previously reported in patients with type 2A von Willebrand disease (Iannuzzi, 1991; Hassenpflug, 2006; Ahmed, 2013) and has been observed in multiple patients with type 2A VWD in our laboratory cohort. Functional studies of the variant in mammalian cells demonstrated loss of high molecular weight multimers (Hassenpflug, 2006) due to hypersensitivity to ADAMTS13 induced increased proteolysis in plasma (Michiels, 2017). To date, this variant has not been reported in the general population (GnomAD, Exome Variant Server). In summary, the collective evidence supports VWF c.4883T>C, p.Ile1628Thr as a pathogenic variant in regards to type 2A von Willebrand disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086808	SCV002046420	pathogenic	not provided	2020-11-14	criteria provided, single submitter	clinical testing	The variant has been reported in symptomatic individuals with von Willebrand Disease (VWD) Type 2A in the published literature (PMIDs: 1673047 (1991), 17681836 (2007), 22102201 (2011), 24712919 (2014), and 31064749 (2019)). Functional studies show that the variant destabilizes the native fold of the protein and is similar in expressional level with normal multimer distribution consistent with VWD 2A (PMIDs: 23110044 (2012) and 27443694 (2016).Therefore, the variant is classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002243602	SCV004175668	pathogenic	von Willebrand disease type 2	2022-04-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086808	SCV004564235	pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	The VWF c.4883T>C; p.Ile1628Thr variant (rs61750584), also known as Ile865Thr when numbered from the mature protein, is reported in the literature in multiple individuals with Type 2A VWD and shown to co-segregate with disease (Ahmad 2014, Downes 2019, Iannuzzi 1991, Sadler 2021). This variant is also classified as pathogenic by multiple sources in the ClinVar database (Variation ID: 284). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 1628 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.703). Based on available information, this variant is considered to be pathogenic. References: Ahmad F et al. Germline de novo mutations and linkage markers vs. DNA sequencing for carrier detection in von Willebrand disease. Haemophilia. 2014 Jul;20(4):e311-7. PMID: 24712919. Downes K et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019 Dec 5;134(23):2082-2091. PMID: 31064749. Iannuzzi MC et al. Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (IIe865 to Thr). Am J Hum Genet. 1991 Apr;48(4):757-63. PMID: 1673047. Sadler B et al. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood. 2021 Jun 10;137(23):3277-3283. PMID: 33556167.
Mayo Clinic Laboratories, Mayo Clinic	RCV000086808	SCV005414033	pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	PP1_strong, PP4, PP5, PM1_supporting, PM2_moderate, PS3_moderate, PS4_moderate
OMIM	RCV000000308	SCV000020452	pathogenic	Von Willebrand disease type 2A	2010-05-01	no assertion criteria provided	literature only
Academic Unit of Haematology, University of Sheffield	RCV000086808	SCV000119014	not provided	not provided		no assertion provided	not provided
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV002243602	SCV002513429	pathogenic	von Willebrand disease type 2	2022-04-26	no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000778377	SCV002515774	pathogenic	Hereditary von Willebrand disease		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004739270	SCV005361190	pathogenic	VWF-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The VWF c.4883T>C variant is predicted to result in the amino acid substitution p.Ile1628Thr. This variant has been reported in the heterozygous state in multiple individuals with von Willebrand Disease (VWD) type 2A (Iannuzzi et al. 1991. PubMed ID: 1673047; Ahmad et al. 2014. PubMed ID: 24712919; Veyradier et al. 2016. PubMed ID: 26986123). A similar variant, c.4883T>A, p.Ile1628Asn, has also been reported to be causative for von Willebrand Disease (VWD) type 2A (Veyradier et al. 2016. PubMed ID: 26986123). The p.Ile1628Thr substitution may affect VWF protein stabilization and biochemical studies indicate it may increase proteolysis of VWF (Interlandi et al. 2012. PubMed ID: 23110044; Hassenpflug et al. 2006. PubMed ID: 16322474). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.