NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000086808.3

Allele description [Variation Report for NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)]

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

Gene:

VWF:von Willebrand factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

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

HGVS:

NC_000012.12:g.6018535A>G
NG_009072.2:g.111136T>C
NM_000552.5:c.4883T>CMANE SELECT
NM_000552.5:c.4883T>C
NP_000543.3:p.Ile1628Thr
LRG_587t1:c.4883T>C
LRG_587:g.111136T>C
LRG_587p1:p.Ile1628Thr
NC_000012.11:g.6127701A>G
NC_000012.11:g.6127701A>G
NG_009072.1:g.111136T>C
NM_000552.2:c.4883T>C
NM_000552.3:c.4883T>C
NM_000552.4:c.4883T>C
P04275:p.Ile1628Thr

Protein change:

I1628T; ILE1628THR

Links:

UniProtKB: P04275#VAR_005817; OMIM: 613160.0001; dbSNP: rs61750584

NCBI 1000 Genomes Browser:

rs61750584

Molecular consequence:

NM_000552.5:c.4883T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000119014	Academic Unit of Haematology, University of Sheffield	no classification provided	not provided	not provided	not provided
SCV002046420	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Nov 14, 2020)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 31064749, 27443694, 24712919, 23110044, 22102201, 17681836, 16322474, 16221672, 1673047, 26467025
SCV004564235	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Sep 29, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000119014

Academic Unit of Haematology, University of Sheffield

no classification provided

not provided

SCV002046420

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Nov 14, 2020)

unknown

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004564235

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Sep 29, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, et al.

Blood. 2019 Dec 5;134(23):2082-2091. doi: 10.1182/blood.2018891192.

PubMed [citation]

PMID:: 31064749
PMCID:: PMC6993014

Diagnostic Differentiation of von Willebrand Disease Types 1 and 2 by von Willebrand Factor Multimer Analysis and DDAVP Challenge Test.

Michiels JJ, Smejkal P, Penka M, Batorova A, Pricangova T, Budde U, Vangenechten I, Gadisseur A.

Clin Appl Thromb Hemost. 2017 Sep;23(6):518-531. doi: 10.1177/1076029616647157. Epub 2016 Jul 21. Review.

PubMed [citation]

PMID:: 27443694

See all PubMed Citations (10)

Details of each submission

From Academic Unit of Haematology, University of Sheffield, SCV000119014.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002046420.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564235.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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