NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys) AND none provided

Clinical significance:Pathogenic (Last evaluated: Dec 16, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001284955.1

Allele description [Variation Report for NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)]

NM_000552.4(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_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
HGVS:
  • NC_000012.12:g.6019496G>A
  • NG_009072.1:g.110175C>T
  • NM_000552.4:c.3922C>T
  • NM_000552.5:c.3922C>T
  • NP_000543.2:p.Arg1308Cys
  • NC_000012.11:g.6128662G>A
  • NM_000552.2:c.3922C>T
  • NM_000552.3: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_000552.4:c.3922C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001471056ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Dec 16, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001471056.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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 general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1308 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. 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. 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. Freitas SDS et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia. 2019 Mar;25(2):e78-e85. 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. 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. Nurden P et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood. 2006 Oct 15;108(8):2587-95. 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. Ranger A et al. Pregnancy in type 2B VWD: a case series. Haemophilia. 2012 May;18(3):406-12.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 30, 2021

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