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NM_000212.3(ITGB3):c.725G>A (p.Arg242Gln) AND Glanzmann thrombasthenia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 7, 2022
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:
RCV002511544.2

Allele description [Variation Report for NM_000212.3(ITGB3):c.725G>A (p.Arg242Gln)]

NM_000212.3(ITGB3):c.725G>A (p.Arg242Gln)

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.725G>A (p.Arg242Gln)
Other names:
NM_000212.3:c.725G>A
HGVS:
  • NC_000017.11:g.47286370G>A
  • NG_008332.2:g.37529G>A
  • NM_000212.3:c.725G>AMANE SELECT
  • NP_000203.2:p.Arg242Gln
  • NP_000203.2:p.Arg242Gln
  • LRG_481t1:c.725G>A
  • LRG_481:g.37529G>A
  • LRG_481p1:p.Arg242Gln
  • NC_000017.10:g.45363736G>A
  • NC_000017.10:g.45363736G>A
  • NM_000212.2:c.725G>A
Protein change:
R242Q
Molecular consequence:
  • NM_000212.3:c.725G>A - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002820940ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2-1)		Pathogenic
(Apr 7, 2022) 		germlinecuration

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Missense mutations in the beta(3) subunit have a different impact on the expression and function between alpha(IIb)beta(3) and alpha(v)beta(3).

Tadokoro S, Tomiyama Y, Honda S, Kashiwagi H, Kosugi S, Shiraga M, Kiyoi T, Kurata Y, Matsuzawa Y.

Blood. 2002 Feb 1;99(3):931-8.

PubMed [citation]
PMID:
11806996

Details of each submission

From ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV002820940.1

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

Description

The NM_000212.3(ITGB3):c.725G>A (p.Arg242Gln) missense variant has a REVEL score of 0.859, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). Surface expression of αIIbβ3 measured by flow cytometry in 293 cells transiently co-transfected with Arg242Gln (here referred to as Arg216Gln) variant β3 and wild type αIIb showed decreased expression at approximately 20% of WT levels indicating that this variant impacts protein function (PMID: 11806996; PS3_moderate). It is absent from gnomAD v2.1.1 (PM2_Supporting). At least 2 GT patients homozygous for this variant have been reported in PMID: 9215749 and PMID: 19691478 (PM3). And At least one patient (Patient GT4 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was severely reduced, as measured by flow cytometry and function was pathological. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3_moderate, PP4_strong, PM2_supporting, PM3, PP3. (VCEP specifications version 2; date of approval 02/03/2022)

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

Last Updated: Sep 29, 2024