VCV000013569.6 - ClinVar

NM_000212.3(ITGB3):c.740G>A (p.Gly247Asp)

Germline

Top reviewed classifications are shown here.

Submission summary:

2 submissions

2 submitters

2 conditions

Reviewed by expert panel

Uncertain Significance

Aug 2024 by ClinGen Platel… FDA Recognized Database

for Glanzmann thrombasthenia

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000212.3(ITGB3):c.740G>A (p.Gly247Asp)

Variation ID: 13569 Accession: VCV000013569.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.32 17: 47286385 (GRCh38) [ NCBI UCSC ] 17: 45363751 (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	Jun 12, 2018	Oct 8, 2024	Aug 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000212.3:c.740G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000203.2:p.Gly247Asp	missense
NM_000212.2(ITGB3):c.740G>A
NC_000017.11:g.47286385G>A
NC_000017.10:g.45363751G>A
NG_008332.2:g.37544G>A
LRG_481:g.37544G>A
	P05106:p.Gly247Asp

... more HGVS ... less HGVS

Protein change

G247D

Other names

G221D

Canonical SPDI

NC_000017.11:47286384:G:A

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: CA123256 UniProtKB: P05106#VAR_069922 OMIM: 173470.0017 dbSNP: rs79560904 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.
ITGB3		No evidence available	No evidence available	GRCh38 GRCh37	622	811

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.
Glanzmann thrombasthenia 2	Pathogenic (1)	no assertion criteria provided	Mar 1, 2010	RCV000014537.31
Glanzmann thrombasthenia	Uncertain significance (1)	reviewed by expert panel	Aug 20, 2024	RCV001580231.3

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 (Aug 20, 2024)	reviewed by expert panel (ClinGen Platelet ACMG Specifications v2-1) Method: curation	Glanzmann thrombasthenia (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV001809868.2 First in ClinVar: Aug 27, 2021 Last updated: Oct 08, 2024	Publications: PubMed (1) PubMed: 20020534 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4385c6b6-e02a-42cd-8333-e5f3b6ce5f5c Comment: The ITGB3 missense variant NM_000212.3:c.740G>A replaces the glycine residue with an aspartate residue (p.Gly247Asp) and is absent from control population databases, including gonmADv4.1.0 (PM2_supporting). The … (more) The ITGB3 missense variant NM_000212.3:c.740G>A replaces the glycine residue with an aspartate residue (p.Gly247Asp) and is absent from control population databases, including gonmADv4.1.0 (PM2_supporting). The variant is predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.963; PP3). The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-19% compared to wild type; PMID: 20020534; PS3_supporting). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3. (less)
Pathogenic (Mar 01, 2010)	no assertion criteria provided Method: literature only	GLANZMANN THROMBASTHENIA 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034788.7 First in ClinVar: Apr 04, 2013 Last updated: Jul 08, 2022	Publications: PubMed (1) PubMed: 20020534 Comment on evidence: In a patient with Glanzmann thrombasthenia (GT2; 619267), Jallu et al. (2010) identified compound heterozygosity for 2 mutations in the ITGB3 gene: a 740G-A transition … (more) In a patient with Glanzmann thrombasthenia (GT2; 619267), Jallu et al. (2010) identified compound heterozygosity for 2 mutations in the ITGB3 gene: a 740G-A transition in exon 5, resulting in a gly221-to-asp (G221D) substitution in the mature protein, and K253M (173470.0016). Both mutations are located in the beta-I domain. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation prevented normal GPIIb/IIIa complex expression on the cell surface consistent with a severe type 1 phenotype. However, specific antibodies detected some residual expression of the IIIa protein. Jallu et al. (2010) postulated that the mutation interferes with correct folding of the protein. (less)

Comment:

The ITGB3 missense variant NM_000212.3:c.740G>A replaces the glycine residue with an aspartate residue (p.Gly247Asp) and is absent from control population databases, including gonmADv4.1.0 (PM2_supporting). The variant is predicted by in silico tools to be damaging to protein function (REVEL score for this variant is 0.963; PP3). The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number of positive cells (estimated to be ~7-19% compared to wild type; PMID: 20020534; PS3_supporting). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3.

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
AlphaIIbbeta3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function.	Jallu V	Human mutation	2010	PMID: 20020534
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4385c6b6-e02a-42cd-8333-e5f3b6ce5f5c	-	-	-	-

Text-mined citations for rs79560904 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000212.3(ITGB3):c.740G>A (p.Gly247Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs79560904 ...