VCV000004155.11 - ClinVar

NM_000173.7(GP1BA):c.763A>G (p.Met255Val)

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.

(5)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000173.7(GP1BA):c.763A>G (p.Met255Val)

Variation ID: 4155 Accession: VCV000004155.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.2 17: 4933367 (GRCh38) [ NCBI UCSC ] 17: 4836662 (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	Apr 4, 2013	Apr 23, 2022	Jul 16, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000173.7:c.763A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000164.5:p.Met255Val	missense
NC_000017.11:g.4933367A>G
NC_000017.10:g.4836662A>G
NG_008767.2:g.6073A>G
LRG_480:g.6073A>G
LRG_480t1:c.763A>G	LRG_480p1:p.Met255Val
	P07359:p.Met255Val

... more HGVS ... less HGVS

Protein change

M255V

Other names

M239V

Canonical SPDI

NC_000017.11:4933366:A:G

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.

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

Links

ClinGen: CA116661 UniProtKB: P07359#VAR_005262 OMIM: 606672.0005 dbSNP: rs121908064 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.
GP1BA		-	-	GRCh38 GRCh37	182	240

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.
Pseudo von Willebrand disease	Pathogenic (2)	criteria provided, single submitter	-	RCV000004372.13
Thrombocytopenia	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851872.9
Impaired ristocetin-induced platelet aggregation	Likely pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851873.9
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 16, 2021	RCV001810831.13

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.
Likely pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Thrombocytopenia Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899905.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Sex: male Ethnicity/Population group: South-Asian
Likely pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Impaired ristocetin-induced platelet aggregation Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899906.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Sex: female Ethnicity/Population group: European
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pseudo von Willebrand disease Affected status: yes Allele origin: de novo, unknown, paternal	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology Accession: SCV002500881.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 Comment: GoldVariant submitters: Loredana Bury, University of Perugia, Department of Medicine and Surgery, Centre for Hemostasis and Thrombosis, Italy; Maha Othman for Seattle Institute for Biomedical … (more) GoldVariant submitters: Loredana Bury, University of Perugia, Department of Medicine and Surgery, Centre for Hemostasis and Thrombosis, Italy; Maha Othman for Seattle Institute for Biomedical and Clinical Research, Seattle, USA; Hemophilia Treatment Center, North Shore Long Island Jewish Health System, Cohen Children’s, Long Island, USA and Niigata University School of Medicine, Niigata, Japan (less)	Publications: PubMed (2) PubMed: 34355501‚ 8384898 Observation 1: Family history: no Ethnicity/Population group: Caucasian Observation 2: Observation 3: Observation 4: Observation 5: Observation 6: Observation 7: Observation 8: Observation 9: Observation 10: Observation 11: Observation 12:
Pathogenic (Jul 16, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002048708.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The GP1BA c.763A>G; p.Met255Val variant (rs121908064), also known as Met239Val in alternate nomenclature, is reported in the literature in multiple individuals affected with pseudo-von Willebrand … (more) The GP1BA c.763A>G; p.Met255Val variant (rs121908064), also known as Met239Val in alternate nomenclature, is reported in the literature in multiple individuals affected with pseudo-von Willebrand disease, also called platelet-type von Willebrand disease (Desai 2015, Giannini 2010, Kunishima 1997, Russell 1993, Takahashi 1995). This variant was observed to co-segregate with disease in several small kindreds (Russell 1993, Takahashi 1995) and was confirmed to have arisen de novo in another family (Kunishima 1997). The p.Met255Val variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 255 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.308). However, functional analyses of patient megakaryocytes with this variant exhibit increased binding to von Willebrand factor (Bury 2019). Based on available information, this variant is considered to be pathogenic. References: Bury L et al. Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. Haematologica. 2019 Jul;104(7):1473-1481. PMID: 30655369. Desai DS et al. Elderly female with a personal and family history of a bleeding disorder. Clin Chem. 2015 Jul;61(7):909-12. PMID: 26116638. Giannini S et al. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica. 2010 Jun;95(6):1021-4. PMID: 19951970. Kunishima S et al. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease. Blood Coagul Fibrinolysis. 1997 Jul;8(5):311-5. PMID: 9282797. Russell SD and Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood. 1993 Apr 1;81(7):1787-91. PMID: 8384898. Takahashi H et al. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease. Blood. 1995 Feb 1;85(3):727-33. PMID: 7833477. (less)
Pathogenic (Apr 01, 1993)	no assertion criteria provided Method: literature only	VON WILLEBRAND DISEASE, PLATELET-TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024543.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 8384898 Comment on evidence: In a father and 2 daughters with pseudo-von Willebrand disease (177820), Russell and Roth (1993) demonstrated an A-to-G transition in codon 239 that resulted in … (more) In a father and 2 daughters with pseudo-von Willebrand disease (177820), Russell and Roth (1993) demonstrated an A-to-G transition in codon 239 that resulted in substitution of valine for methionine (M239V). The abnormal receptor displayed increased affinity for its ligand, von Willebrand factor. (less)

Comment:

The GP1BA c.763A>G; p.Met255Val variant (rs121908064), also known as Met239Val in alternate nomenclature, is reported in the literature in multiple individuals affected with pseudo-von Willebrand disease, also called platelet-type von Willebrand disease (Desai 2015, Giannini 2010, Kunishima 1997, Russell 1993, Takahashi 1995). This variant was observed to co-segregate with disease in several small kindreds (Russell 1993, Takahashi 1995) and was confirmed to have arisen de novo in another family (Kunishima 1997). The p.Met255Val variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 255 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.308). However, functional analyses of patient megakaryocytes with this variant exhibit increased binding to von Willebrand factor (Bury 2019). Based on available information, this variant is considered to be pathogenic. References: Bury L et al. Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. Haematologica. 2019 Jul;104(7):1473-1481. PMID: 30655369. Desai DS et al. Elderly female with a personal and family history of a bleeding disorder. Clin Chem. 2015 Jul;61(7):909-12. PMID: 26116638. Giannini S et al. Diagnosis of platelet-type von Willebrand disease by flow cytometry. Haematologica. 2010 Jun;95(6):1021-4. PMID: 19951970. Kunishima S et al. De novo mutation of the platelet glycoprotein Ib alpha gene in a patient with pseudo-von Willebrand disease. Blood Coagul Fibrinolysis. 1997 Jul;8(5):311-5. PMID: 9282797. Russell SD and Roth GJ. Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor. Blood. 1993 Apr 1;81(7):1787-91. PMID: 8384898. Takahashi H et al. Substitution of Val for Met at residue 239 of platelet glycoprotein Ib alpha in Japanese patients with platelet-type von Willebrand disease. Blood. 1995 Feb 1;85(3):727-33. PMID: 7833477.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis.	Megy K	Journal of thrombosis and haemostasis : JTH	2021	PMID: 34355501
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
Pseudo-von Willebrand disease: a mutation in the platelet glycoprotein Ib alpha gene associated with a hyperactive surface receptor.	Russell SD	Blood	1993	PMID: 8384898

Text-mined citations for rs121908064 ...

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_000173.7(GP1BA):c.763A>G (p.Met255Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908064 ...