NM_000552.5(VWF):c.3922C>T (p.Arg1308Cys) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 21, 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:: RCV000086703.16

Allele description [Variation Report for NM_000552.5(VWF):c.3922C>T (p.Arg1308Cys)]

NM_000552.5(VWF):c.3922C>T (p.Arg1308Cys)

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.3922C>T (p.Arg1308Cys)

Other names:

p.R1308C

HGVS:

NC_000012.12:g.6019496G>A
NG_009072.2:g.110175C>T
NM_000552.5:c.3922C>TMANE SELECT
NM_000552.5:c.3922C>T
NP_000543.3:p.Arg1308Cys
LRG_587t1:c.3922C>T
LRG_587:g.110175C>T
LRG_587p1:p.Arg1308Cys
NC_000012.11:g.6128662G>A
NG_009072.1:g.110175C>T
NM_000552.2:c.3922C>T
NM_000552.3:c.3922C>T
NM_000552.4:c.3922C>T
P04275:p.Arg1308Cys

Protein change:

R1308C; ARG1308CYS

Links:

UniProtKB: P04275#VAR_005795; OMIM: 613160.0006; dbSNP: rs61749387

NCBI 1000 Genomes Browser:

rs61749387

Molecular consequence:

NM_000552.5:c.3922C>T - 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
SCV000118907	Academic Unit of Haematology, University of Sheffield	no classification provided	not provided	not provided	not provided
SCV000889912	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 26, 2021)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 16246252, 17155947, 9723578, 25851809, 26345337, 23179108, 2010538, 25431025, 26456374, 8865541, 20409624, 1419803, 1761120, 30817071, 22077376, 31939074, 31064749, 26467025
SCV001471056	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Feb 21, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000118907

Academic Unit of Haematology, University of Sheffield

no classification provided

not provided

SCV000889912

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Aug 26, 2021)

unknown

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

SCV001471056

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Feb 21, 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

Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding.

Baronciani L, Federici AB, Beretta M, Cozzi G, Canciani MT, Mannucci PM.

J Thromb Haemost. 2005 Dec;3(12):2689-94. Epub 2005 Oct 25.

PubMed [citation]

PMID:: 16246252

Biochemical characterization of a recombinant von Willebrand factor (VWF) with combined type 2B and type 1 defects in the VWF gene in two patients with a type 2A phenotype of von Willebrand disease.

Baronciani L, Federici AB, Cozzi G, Canciani MT, Mannucci PM.

J Thromb Haemost. 2007 Feb;5(2):282-8. Epub 2006 Dec 7.

PubMed [citation]

PMID:: 17155947

See all PubMed Citations (18)

Details of each submission

From Academic Unit of Haematology, University of Sheffield, SCV000118907.1

#	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, SCV000889912.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The variant has been reported in multiple individuals with type 2B von Willebrand disease in the published literature (PMIDs: 31939074 (2020), 30817071 (2019), 1419803 (1992), and 2010538 (1991)). It has been shown to result in enhanced sensitivity to ADAMT13-mediated proteolysis (PMID: 26345337 (2015)), increased affinity for GpIbα, increased absence of high molecular weight multimers (PMIDs: 2010538 (1991), 16246252 (2005)), 23179108 (2013), 17155947 (2007)), and a reduced binding to collagen type I and III (PMID: 16246252 (2005)). 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, SCV001471056.2

#	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.3922C>T; p.Arg1308Cys variant (rs61749387), also known as R545C, is reported in the literature in multiple individuals affected with von Willebrand disease type 2B (Ahmad 2013, Baronciani 2005, Freitas 2019, Randi 1991, Ranger 2012). This variant is reported in ClinVar (Variation ID: 289), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1308 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.673). Additionally, other amino acid substitutions at this codon (Leu, Pro, Ser, His) have been reported in individuals with von Willebrand disease type 2B (Baronciani 2005, Hatta 2015, Meyer 1997, Nurden 2006). Based on available information, this variant is considered to be pathogenic. References: Ahmad F et al. Characterisation of mutations and molecular studies of type 2 von Willebrand disease. Thromb Haemost. 2013 Jan;109(1):39-46. PMID: 23179108 Baronciani L et al. Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding. J Thromb Haemost. 2005 Dec;3(12):2689-94. PMID: 16246252 Freitas SDS et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia. 2019 Mar;25(2):e78-e85. PMID: 30817071 Hatta K et al. A family having type 2B von Willebrand disease with a novel VWF p.R1308S mutation: Detection of characteristic platelet aggregates on peripheral blood smears as the key aspect of diagnosis. Thromb Res. 2015 Oct;136(4):813-7. PMID: 26278967 Meyer D et al. Gene defects in 150 unrelated French cases with type 2 von Willebrand disease: from the patient to the gene. INSERM Network on Molecular Abnormalities in von Willebrand Disease. Thromb Haemost. 1997 Jul;78(1):451-6. PMID: 9198195 Nurden P et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood. 2006 Oct 15;108(8):2587-95. PMID: 16720832 Randi AM et al. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences. J Clin Invest. 1991 Apr;87(4):1220-6. PMID: 2010538 Ranger A et al. Pregnancy in type 2B VWD: a case series. Haemophilia. 2012 May;18(3):406-12. PMID: 22077376

#	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: Apr 20, 2024

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