VCV000100240.35 - ClinVar

NM_000552.5(VWF):c.2771G>A (p.Arg924Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(5); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000552.5(VWF):c.2771G>A (p.Arg924Gln)

Variation ID: 100240 Accession: VCV000100240.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.31 12: 6031493 (GRCh38) [ NCBI UCSC ] 12: 6140659 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 25, 2014	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000552.5:c.2771G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000543.3:p.Arg924Gln	missense
NC_000012.12:g.6031493C>T
NC_000012.11:g.6140659C>T
NG_009072.2:g.98178G>A
LRG_587:g.98178G>A
LRG_587t1:c.2771G>A	LRG_587p1:p.Arg924Gln

... more HGVS ... less HGVS

Protein change

R924Q

Other names

p.Arg924Gln
p.R924Q

Canonical SPDI

NC_000012.12:6031492:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00679 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00562

1000 Genomes Project 0.00679

The Genome Aggregation Database (gnomAD), exomes 0.01053

Exome Aggregation Consortium (ExAC) 0.01063

Trans-Omics for Precision Medicine (TOPMed) 0.01121

The Genome Aggregation Database (gnomAD) 0.01237

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01499

Links

ClinGen: CA228368 dbSNP: rs33978901 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
VWF		-	-	GRCh38 GRCh37	1546	1600

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jun 1, 2024	RCV000086632.32
von Willebrand disease type 3	Benign (2)	criteria provided, single submitter	Dec 5, 2021	RCV001787051.10
von Willebrand disease type 2	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 6, 2022	RCV002243720.11
von Willebrand disease type 1	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 6, 2022	RCV002243719.11
Hereditary von Willebrand disease	Uncertain significance (1)	criteria provided, single submitter	Dec 13, 2019	RCV003447494.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Feb 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002541192.2 First in ClinVar: Jul 09, 2022 Last updated: Jan 26, 2024	Number of individuals with the variant: 7
Benign (Nov 29, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157484.4 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004132420.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: VWF: BP4, BS1, BS2 Number of individuals with the variant: 4
Benign (Dec 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	von Willebrand disease type 3 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002514654.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Benign (Dec 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	von Willebrand disease type 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002514655.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Benign (Dec 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	von Willebrand disease type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002514652.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Uncertain significance (May 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	von Willebrand disease type 2 Affected status: yes Allele origin: germline	Laboratory of Hematology, Radboud University Medical Center Study: WIN study Accession: SCV002546266.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Number of individuals with the variant: 4
Uncertain significance (May 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	von Willebrand disease type 1 Affected status: yes Allele origin: germline	Laboratory of Hematology, Radboud University Medical Center Study: WIN study Accession: SCV002546264.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022	Number of individuals with the variant: 10
Uncertain significance (Dec 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary von Willebrand disease Affected status: unknown Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175294.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023
Likely benign (Mar 29, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889898.5 First in ClinVar: Feb 25, 2014 Last updated: Jan 06, 2024	Publications: PubMed (20) PubMed: 22995991‚ 33807613‚ 29220693‚ 22102201‚ 20851871‚ 21534937‚ 26270243‚ 27007659‚ 22871923‚ 32722784‚ 30690834‚ 16894469‚ 22197721‚ 19624459‚ 23340442‚ 20492463‚ 12588349‚ 18841300‚ 21371195‚ 21410641
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005213668.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (Nov 01, 2020)	no assertion criteria provided Method: clinical testing	von Willebrand disease type 3 Affected status: yes Allele origin: germline	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Study: Type 3 Von Willebrand International Registries Inhibitor Prospective Study (3WINTERS-IPS) Accession: SCV001572669.1 First in ClinVar: May 01, 2021 Last updated: May 01, 2021	Comment: ClinGen Pathogenicity Calculator
Benign (Apr 26, 2022)	no assertion criteria provided Method: clinical testing	von Willebrand disease type 2 Affected status: yes Allele origin: germline	Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Accession: SCV002513402.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Academic Unit of Haematology, University of Sheffield Accession: SCV000118836.1 First in ClinVar: Feb 25, 2014 Last updated: Feb 25, 2014
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Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing.	Gindele R	Life (Basel, Switzerland)	2021	PMID: 33807613
Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D'D3 and D4 domains.	Sacco M	Blood advances	2020	PMID: 32722784
Challenges in diagnosis of von Willebrand disease in the presence of combined mutations of different genes.	Nava T	Haemophilia : the official journal of the World Federation of Hemophilia	2019	PMID: 30690834
Type 1 von Willebrand disease due to a vicinal cysteine loss (p.C524Y) disclosed after a thrombotic episode.	Daidone V	Thrombosis research	2018	PMID: 29220693
Whole Exome Sequencing in Patients with the Cuticular Drusen Subtype of Age-Related Macular Degeneration.	Duvvari MR	PloS one	2016	PMID: 27007659
Angiogenic characteristics of blood outgrowth endothelial cells from patients with von Willebrand disease.	Groeneveld DJ	Journal of thrombosis and haemostasis : JTH	2015	PMID: 26270243
Collagen binding provides a sensitive screen for variant von Willebrand disease.	Flood VH	Clinical chemistry	2013	PMID: 23340442
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients.	Yadegari H	Thrombosis and haemostasis	2012	PMID: 22871923
VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population.	Bellissimo DB	Blood	2012	PMID: 22197721
Diagnosis and management of von Willebrand disease in a single institution of Argentina.	Woods AI	Seminars in thrombosis and hemostasis	2011	PMID: 22102201
Variation in the VWF gene in Swedish patients with type 1 von Willebrand Disease.	Johansson AM	Annals of human genetics	2011	PMID: 21534937
Large deletions identified in patients with von Willebrand disease using multiple ligation-dependent probe amplification.	Yadegari H	Journal of thrombosis and haemostasis : JTH	2011	PMID: 21410641
Validation of the first commercial ELISA for type 2N von Willebrand's disease diagnosis.	Veyradier A	Haemophilia : the official journal of the World Federation of Hemophilia	2011	PMID: 21371195
Polymorphic variation within the VWF gene contributes to the failure to detect mutations in patients historically diagnosed with type 1 von Willebrand disease from the MCMDM-1VWD cohort.	Hampshire DJ	Haematologica	2010	PMID: 20851871
von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.	Hickson N	Journal of thrombosis and haemostasis : JTH	2010	PMID: 20492463
An assessment of the pathogenic significance of the R924Q von Willebrand factor substitution.	Berber E	Journal of thrombosis and haemostasis : JTH	2009	PMID: 19624459
Is VWF R924Q a benign polymorphism, a marker of a null allele or a factor VIII-binding defect? The debate continues with results from the UKHCDO VWD study.	Lester W	Thrombosis and haemostasis	2008	PMID: 18841300
R924Q substitution encoded within exon 21 of the von Willebrand factor gene related to mild bleeding phenotype.	Casais P	Thrombosis and haemostasis	2006	PMID: 16894469
Two novel mutations, Q1053H and C1060R, located in the D3 domain of von Willebrand factor, are responsible for decreased FVIII-binding capacity.	Hilbert L	British journal of haematology	2003	PMID: 12588349
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Text-mined citations for rs33978901 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000552.5(VWF):c.2771G>A (p.Arg924Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs33978901 ...