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:c.416C>T

CA399806036

1210192 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2bebe3f2-ae3a-49e6-97f4-da340eeb4bea

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000419.5:c.416C>T

NC_000017.11:g.44385709G>A

CM000679.2:g.44385709G>A

NC_000017.10:g.42463077G>A

CM000679.1:g.42463077G>A

NC_000017.9:g.39818603G>A

NG_008331.1:g.8797C>T

ENST00000262407.6:c.416C>T

ENST00000262407.5:c.416C>T

ENST00000592944.1:n.101C>T

NM_000419.3:c.416C>T

NM_000419.4:c.416C>T

Likely Pathogenic

PM3 PP4_Strong PM2_Supporting PP3

Evidence Links 0

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 ITGA2B missense variant NM_000419.5:c.416C>T replaces the alanine residue with a valine residue (p.Ala139Val). This variant is absent from population databases including gnomADv4.1.0 (PM2_supporting), but has been observed in homozygosity in two individuals suspected to have Glanzmann's thrombasthenia (GT) (Patient PF in PMID: 12083483; GT22 in PMID: 16463284) (PM3). At least one of these individuals (Patient PF in PMID: 12083483) has a phenotype specific for GT (PP4_strong); bleeding phenotype strongly indicative of Glanzmann's thrombasthenia; impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin; <10% expression of GPIIb/IIIa; direct sequencing of all coding regions and intron/exon boundaries of ITGA2B and ITGB3. The variant is predicted by in silico tools to be damaging to protein function (REVEL score 0.794; PP3). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PM3, PP3, PP4_strong.

PM3

This variant was reported in homozygosity in two individuals (Patient PF in PMID: 12083483; GT22 in PMID: 16463284), sufficient to apply PM3.

PP4_Strong

This variant was reported in homozygosity in two individuals (Patient PF in PMID: 12083483; GT22 in PMID: 16463284). At least one of these individuals (Patient PF in PMID: 12083483) meets all requirements for PP4 at an upgraded strength of strong (PP4_strong): bleeding phenotype strongly indicative of Glanzmann's thrombasthenia; impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin; <10% expression of GPIIb/IIIa; direct sequencing of all coding regions and intron/exon boundaries of ITGA2B and ITGB3.

PM2_Supporting

This variant is absent from gnomAv4.1.0 (PM2_supporting)

PP3

The REVEL score for this variant is 0.794, exceeding the VCEP-established threshold of ≥0.7 to support a deleterious effect.

Curation History

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