VCV000050227.4 - ClinVar

NM_000212.3(ITGB3):c.2245G>C (p.Asp749His)

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.

(1)

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

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000212.3(ITGB3):c.2245G>C (p.Asp749His)

Variation ID: 50227 Accession: VCV000050227.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.32 17: 47307581 (GRCh38) [ NCBI UCSC ] 17: 45384947 (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	Jul 8, 2022	Jul 8, 2022	Apr 1, 2008

HGVS

Nucleotide	Protein	Molecular consequence
NM_000212.3:c.2245G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000203.2:p.Asp749His	missense
NC_000017.11:g.47307581G>C
NC_000017.10:g.45384947G>C
NG_008332.2:g.58740G>C
LRG_481:g.58740G>C
LRG_481t1:c.2245G>C	LRG_481p1:p.Asp749His
	P05106:p.Asp749His

... more HGVS ... less HGVS

Protein change

D749H

Other names

D723H

Canonical SPDI

NC_000017.11:47307580:G:C

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

dbSNP: rs398122372 ClinGen: CA143709 UniProtKB: P05106#VAR_069924 OMIM: 173470.0018 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 18065693 to determine the location of this allele on the current reference sequence. The mutation shown in the Fig. 1B sequencing can be mapped to NM_000212.2:c.2245G>C, which translates to NP_000203.2:p.Asp749His and not Asp723His.

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.
ITGB3		No evidence available	No evidence available	GRCh38 GRCh37	622	811
EFCAB13-DT	-	-	-	GRCh38	-	127

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.
Bleeding disorder, platelet-type, 24	Pathogenic (1)	no assertion criteria provided	Apr 1, 2008	RCV000043480.25

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.
Pathogenic (Apr 01, 2008)	no assertion criteria provided Method: literature only	BLEEDING DISORDER, PLATELET-TYPE, 24 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000067292.5 First in ClinVar: May 06, 2013 Last updated: Jul 08, 2022	Publications: PubMed (1) PubMed: 18065693 Comment on evidence: In 5 members of a family with autosomal dominant platelet-type bleeding disorder-24 manifest as congenital macrothrombocytopenia (BDPLT24; 187800), Ghevaert et al. (2008) identified a heterozygous … (more) In 5 members of a family with autosomal dominant platelet-type bleeding disorder-24 manifest as congenital macrothrombocytopenia (BDPLT24; 187800), Ghevaert et al. (2008) identified a heterozygous c.2245G-C transversion in exon 14 of the ITGB3 gene, resulting in an asp723-to-his (D723H) substitution in the membrane proximal cytoplasmic segment of the protein. Molecular modeling indicated that the mutation changed the electrostatic surface potential, consistent with the disruption of a conserved salt bridge with R995 in the ITGA2B gene (607759). The D723H mutation was not found in unaffected family members or in 1,639 controls. In vitro functional expression assays in CHO cells showed that the mutant protein was constitutively active. There was spontaneously increased binding of the PAC-1 antibody, which specifically recognizes the activated form of the GPIIb/IIIa complex, as well as increased adhesion to von Willebrand factor (VWF) in static conditions and increased binding to fibrinogen under shear stress compared to wildtype. The mutant protein also led to the formation of large proplatelet-like protrusions in CHO cells and in patient megakaryocytes in the presence of fibrinogen. The findings suggested that constitutive partial activation of the mutant receptor caused abnormal sizing of platelets during formation, resulting in thrombocytopenia due to increased platelet turnover. GPIIb/IIIa expression on platelets was normal, and none of the affected individuals had bleeding abnormalities; the defect in the proband was an incidental finding. (less)

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
A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia.	Ghevaert C	Blood	2008	PMID: 18065693

Text-mined citations for rs398122372 ...

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 Jul 09, 2022

ClinVar Genomic variation as it relates to human health

NM_000212.3(ITGB3):c.2245G>C (p.Asp749His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398122372 ...