rs61750584

Positions:

• chr12-6018535-A-G
• chr12-6018535-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4 PP1_Moderate PS3_Supporting PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000552.5(VWF):c.4883T>C is a missense variant in VWF predicted to cause substitution of isoleucine by threonine at amino acid 1628. The Grpmax filtering allele frequency in gnomAD v4.1 is 2.800e-7 (based on 2/1179884 alleles in the European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for (PM2_Supporting). The computational predictor REVEL gives a score of 0.703, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). At least sixteen patients with this variant have been diagnosed with VWD Type 2A, of whom nine are documented to have displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity (measured by VWF:RCo) low VWF:RCo/ VWF:Ag ratio, and absence of high-molecular weight VWF multimers, which together are highly specific for VWD type 2A (PP4_Moderate, PMID:28536718, VCEP member-provided data). Thirteen total probands have been described in sufficient detail to establish a phenotype specific to VWD type 2A (PS4_VeryStrong, PMID:28536718, VCEP member-provided data, PMID:28971901). The variant has been reported to segregate with VWD type 2A through 6 affected meioses from 1 family and 3 affected meioses in another (PP1_Moderate; PMID:1673047, PMID:28971901). Proteolysis assays of an exogenously expressed VWF fragment showed higher susceptibility of the variant protein to ADAMTS13 proteolysis under non-denaturing conditions (PMID:16221672, PMID:16322474, PMID:23110044), indicating that this variant has a damaging effect on protein function (PS3_Supporting). The variant protein exhibited normal multimer distribution (PMID:16322474) and secretion rate (PMID:8123844) in vitro. In summary, this variant meets the criteria to be classified as Pathogenic for von Willebrand disease type 2A. ACMG/AMP criteria applied as specified by the ClinGen von Willebrand disease Variant Curation Expert Panel: PS3_supporting, PS4, PP1_Moderate, PM2_Supporting, PP3, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114115/MONDO:0015628/081

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.30

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWF	NM_000552.5	c.4883T>C	p.Ile1628Thr	missense_variant	28/52	ENST00000261405.10
VWF	XM_047429501.1	c.4883T>C	p.Ile1628Thr	missense_variant	28/52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWF	ENST00000261405.10	c.4883T>C	p.Ile1628Thr	missense_variant	28/52	1	NM_000552.5	P1
VWF	ENST00000538635.5	n.421-24601T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461722 Hom.: 0 Cov.: 40 AF XY: 0.00000275 AC XY: 2 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary von Willebrand disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 22, 2018	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. -
Pathogenic, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Feb 01, 2019	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 29, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 14, 2020	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. -
not provided, no classification provided	literature only	Academic Unit of Haematology, University of Sheffield	-	- -

von Willebrand disease type 2 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Apr 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 07, 2022	- -

Von Willebrand disease type 2A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Versiti Diagnostic Laboratories, Versiti, Inc	Jan 21, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.88	N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.27	B
Vest4		0.83
MutPred		0.79		Gain of catalytic residue at V1630 (P = 5e-04);
MVP		0.90
MPC		0.34
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61750584; hg19: chr12-6127701;