Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000419.5(ITGA2B):c.1361G>A (p.Gly454Asp)

CA399803524

977127 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 7874e234-df85-40e5-a3db-fa1c8adbf22a

Approved on: 2025-04-15

Published on: 2025-05-13

HGVS expressions

NM_000419.5(ITGA2B):c.1361G>A (p.Gly454Asp)

NM_000419.5:c.1361G>A

NC_000017.11:g.44380911C>T

CM000679.2:g.44380911C>T

NC_000017.10:g.42458279C>T

CM000679.1:g.42458279C>T

NC_000017.9:g.39813805C>T

NG_008331.1:g.13595G>A

ENST00000262407.6:c.1361G>A

ENST00000648408.1:c.792G>A

ENST00000262407.5:c.1361G>A

ENST00000592226.5:n.601G>A

ENST00000592462.5:n.156G>A

NM_000419.3:c.1361G>A

NM_000419.4:c.1361G>A

Likely Pathogenic

PS3_Supporting PM3_Supporting PP4_Strong PM2_Supporting PP3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.1361G>A (p.Gly454Asp) variant has been reported, in the homozygous state, in at least one GT proband (P3 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry (PP4_strong). Surface expression of αIIbβ3 measured by flow cytometry in COS-7 cells transiently co-transfected with Gly454Asp variant αIIb and wild type β3 showed impaired expression levels. There is a clear decrease in percent positive cells with near absence interpreted as <25% (PMID: 34275420; PS3_supporting). The variant is predicted deleterious (REVEL score 0.812). This variant is absent from gnomAD v2.1.1 and present in gnomADv4.1 on 1 allele in the "Remaining" genetic ancestry group (PM2_supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3_supporting, PP4_strong, PS3_supporting, and PP3.

PS3_Supporting

Surface expression of αIIbβ3 measured by flow cytometry in COS-7 cells transiently co-transfected with Gly454Asp variant αIIb and wild type β3 showed impaired expression levels. There is a clear decrease in percent positive cells shown in Figure 1, with near absence interpreted as <25% (PMID: 34275420; PS3_supporting). This evidence was downgraded to PS3_Supporting because the level of αIIb, β3, and αIIbβ3 cell surface expression was not reported, only whether cells were positive or negative for surface αIIb, β3, and αIIbβ3.

PM3_Supporting

P3 (PMID: 34275420) is homozygous for this variant. 0.5pt (PM3_supporting)

PP4_Strong

At least one patient (P3 in PMID: 34275420) 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 reduced to <5%, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong)

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and present in gnomADv4.1 on 1 allele in the "Remaining" genetic ancestry group.

PP3

The REVEL score for this variant is 0.812, exceeding the VCEP-established threshold of >0.7 to support a deleterious effect.

Curation History

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