NM_000552.5(VWF):c.6859C>T (p.Arg2287Trp) AND not provided

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Mar 15, 2024
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:: RCV000086862.39

Allele description [Variation Report for NM_000552.5(VWF):c.6859C>T (p.Arg2287Trp)]

NM_000552.5(VWF):c.6859C>T (p.Arg2287Trp)

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.6859C>T (p.Arg2287Trp)

Other names:

p.Arg2287Trp

HGVS:

NC_000012.12:g.5985605G>A
NG_009072.2:g.144066C>T
NM_000552.5:c.6859C>TMANE SELECT
NP_000543.2:p.Arg2287Trp
NP_000543.3:p.Arg2287Trp
LRG_587t1:c.6859C>T
LRG_587:g.144066C>T
LRG_587p1:p.Arg2287Trp
NC_000012.11:g.6094771G>A
NG_009072.1:g.144066C>T
NM_000552.2:c.6859C>T
NM_000552.3:c.6859C>T
NM_000552.4:c.6859C>T

Protein change:

R2287W

Links:

dbSNP: rs61750625

NCBI 1000 Genomes Browser:

rs61750625

Molecular consequence:

NM_000552.5:c.6859C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Mus musculus sushi domain containing 4 (Susd4), mRNA
Mus musculus sushi domain containing 4 (Susd4), mRNA
gi|141802284|ref|NM_144796.3|

Nucleotide
Homo sapiens kinesin light chain 4 (KLC4), transcript variant 2, mRNA
Homo sapiens kinesin light chain 4 (KLC4), transcript variant 2, mRNA
gi|1676324986|ref|NM_201522.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000119068	Academic Unit of Haematology, University of Sheffield	no classification provided	not provided	not provided	not provided
SCV000574916	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Oct 1, 2016)	germline	clinical testing	Citation Link,
SCV000706251	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Feb 6, 2017)	germline	clinical testing	Citation Link,
SCV001134917	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 4, 2023)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16985174, 19566550, 22197721, 23216583, 23340442, 23690449, 25564403, 33556167, 31035301, 31968368, 26467025
SCV002027853	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 15, 2024)	germline	clinical testing	Citation Link,
SCV002541186	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799239	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Sep 1, 2023)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	5	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	germline	yes	1	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

Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD).

Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, Meyer D, Mazurier C, Goudemand J, Schneppenheim R, Budde U, Ingerslev J, Habart D, Vorlova Z, Holmberg L, Lethagen S, Pasi J, Hill F, Hashemi Soteh M, Baronciani L, Hallden C, Guilliatt A, et al.

Blood. 2007 Jan 1;109(1):112-21. Epub 2006 Sep 19. Erratum in: Blood. 2008 Mar 15;111(6):3299-300.

PubMed [citation]

PMID:: 16985174

Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study.

Eikenboom J, Hilbert L, Ribba AS, Hommais A, Habart D, Messenger S, Al-Buhairan A, Guilliatt A, Lester W, Mazurier C, Meyer D, Fressinaud E, Budde U, Will K, Schneppenheim R, Obser T, Marggraf O, Eckert E, Castaman G, Rodeghiero F, Federici AB, Batlle J, et al.

J Thromb Haemost. 2009 Aug;7(8):1304-12. doi: 10.1111/j.1538-7836.2009.03486.x. Epub 2009 Jun 30.

PubMed [citation]

PMID:: 19566550

See all PubMed Citations (12)

Details of each submission

From Academic Unit of Haematology, University of Sheffield, SCV000119068.1

#	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 CeGaT Center for Human Genetics Tuebingen, SCV000574916.31

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

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

From Eurofins Ntd Llc (ga), SCV000706251.2

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

#	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		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134917.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

he frequency of this variant in the general population, 0.008 (199/24962 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with Type 1 or Type 2A von Willebrand disease (vWD) (PMID: 16985174 (2007), 23340442 (2013)), but it has also been reported in healthy individuals (PMID: 22197721 (2012), 23216583 (2013)). In in-vivo functional studies, this variant caused mild intracellular retention and impaired secretion of VWF protein (PMID: 16985174 (2007), 19566550 (2009), 23340442 (2013), 31035301 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 GeneDx, SCV002027853.4

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

Description

Identified in multiple individuals with different subtypes of von Willebrand disease, including type 1, type 2M, and type 2A in the published literature, however, many individuals had other variants identified in VWF, and additional clinical or segregation information to support pathogenicity was not provided (PMID: 16321553, 16985174, 23340442); Published functional studies demonstrate a damaging effect with mild reduction in the amount of secreted VWF protein (PMID: 19566550); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19506359, 20981092, 24482836, 18344424, 16985174, 22197721, 22995991, 23216583, 23340442, 23690449, 19566550, 33556167, 35552711, 35734101, 16321553)

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV002541186.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

PS3

#	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		4	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799239.3

#	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.6859C>T; p.Arg2287Trp variant (rs61750625) is reported in the literature in individuals affected with von Willebrand disease (Goodeve 2007, Eikenboom 2009, Flood 2013), but has also been found in unaffected controls (Bellissimo 2012). Functional analyses of the variant protein show slightly impaired secretion (Flood 2013). This variant is reported in ClinVar (Variation ID: 100450) and is found in the African population with an allele frequency of 0.8% (199/24962 alleles, including 1 homozygote) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.34). Due to limited information, the clinical significance of the p.Arg2287Trp variant is uncertain at this time. References: Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Eikenboom J et al. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost. 2009 Aug;7(8):1304-12. PMID: 19566550. Flood VH et al. Collagen binding provides a sensitive screen for variant von Willebrand disease. Clin Chem. 2013 Apr;59(4):684-91. PMID: 23340442. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174.

#	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 8, 2024

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