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NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro) AND Glanzmann thrombasthenia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 10, 2020
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV001290457.1

Allele description [Variation Report for NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro)]

NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro)

Gene:
ITGB3:integrin subunit beta 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q21.32
Genomic location:
Preferred name:
NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro)
HGVS:
  • NC_000017.11:g.47286310T>C
  • NG_008332.2:g.37469T>C
  • NM_000212.3:c.665T>CMANE SELECT
  • NP_000203.2:p.Leu222Pro
  • LRG_481:g.37469T>C
  • NC_000017.10:g.45363676T>C
  • NC_000017.10:g.45363676T>C
Protein change:
L222P
Links:
dbSNP: rs79208797
NCBI 1000 Genomes Browser:
rs79208797
Molecular consequence:
  • NM_000212.3:c.665T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Glanzmann thrombasthenia
Synonyms:
PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY; Thrombasthenia of Glanzmann and Naegeli; Glanzmann thrombasthenia type A; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0100326; MedGen: C0040015; Orphanet: 849; OMIM: PS273800

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001478491ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2)		Pathogenic
(Nov 10, 2020) 		germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

A naturally occurring point mutation in the beta3 integrin MIDAS-like domain affects differently alphavbeta3 and alphaIIIbbeta3 receptor function.

Morel-Kopp MC, Melchior C, Chen P, Ammerlaan W, Lecompte T, Kaplan C, Kieffer N.

Thromb Haemost. 2001 Dec;86(6):1425-34.

PubMed [citation]
PMID:
11776310

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

Nurden AT, Pillois X, Fiore M, Alessi MC, Bonduel M, Dreyfus M, Goudemand J, Gruel Y, Benabdallah-Guerida S, Latger-Cannard V, Négrier C, Nugent D, Oiron RD, Rand ML, Sié P, Trossaert M, Alberio L, Martins N, Sirvain-Trukniewicz P, Couloux A, Canault M, Fronthroth JP, et al.

Hum Mutat. 2015 May;36(5):548-61. doi: 10.1002/humu.22776.

PubMed [citation]
PMID:
25728920

Details of each submission

From ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV001478491.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

NM_000212.3(ITGB3):c.665T>C (p.Leu222Pro) is a missense variant which has been previously reported in at least two symptomatic individuals who meet the diagnostic criteria for the GT phenotype (PMIDs:25728920, 11897046). This variant is present at an extremely low MAF of 0.000064 in the Non-Finnish European subpopulation in gnomAD. This variant has been predicted to be deleterious by multiple in silico tools (REVEL score = 0.97). This variant has been reported to occur in the homozygous state in one proband as well as in heterozygous state with another pathogenic variant (p.Cys624Tyr) in a non related proband. Functional studies have demonstrated a deleterious effect on the gene product, preventing the binding of soluble fibrinogen and fibrinogen mimetic antibodies (PMID: 11776310). This variant meets GT specific criteria for PS3, PP4_strong, PM2_supporting, PP3 and PM3_supporting and is therefore classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2024