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_000419.4:c.2951C>A

CA399790180

952998 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 6a7fde6e-8154-4494-85af-3ead01f92afe

Approved on: 2023-09-07

Published on: 2023-09-21

HGVS expressions

NM_000419.4:c.2951C>A

NC_000017.11:g.44374463G>T

CM000679.2:g.44374463G>T

NC_000017.10:g.42451831G>T

CM000679.1:g.42451831G>T

NC_000017.9:g.39807357G>T

NG_008331.1:g.20043C>A

ENST00000262407.6:c.2951C>A

ENST00000648408.1:c.2374+196C>A

ENST00000262407.5:c.2951C>A

ENST00000587295.5:c.253+1370C>A

ENST00000588098.1:c.37+196C>A

ENST00000592462.5:n.2650C>A

NM_000419.3:c.2951C>A

NM_000419.5:c.2951C>A

NM_000419.5(ITGA2B):c.2951C>A (p.Thr984Lys)

Likely Pathogenic

PP4_Strong PM3_Supporting PP3 PM2_Supporting

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The missense variant NM_000419.5(ITGA2B):c.2951C>A (p.Thr984Lys) has been reported in one homozygous proband (PM3_supporting) who meets the criteria for PP4_strong, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and <5% surface expression of αIIbβ3 measured by flow cytometry (PMID: 25728920). The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). Multiple lines of computational evidence support a deleterious effect with a REVEL score of 0.774 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PP3, PM3_supporting, PP4_strong.

PP4_Strong

One patient has been described with the Arg169Ter variant who meets the criteria for PP4, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and <5% surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

Patient GT72, homozygous for Thr984Lys, had a history of mucocutaneous bleeding (marked bleeding syndrome with epistaxis, ecchymoses, gingivorrhagia, menorrhagia) and a WHO bleeding score of 3. There was absent platelet aggregation with ADP and severely reduced with at least two additional agonists but normal ristocetin-induced aggregation. There was <5% αIIbβ3 platelet surface expression confirmed by flow cytometry. PubMed:25728920

PM3_Supporting

One homozygous individual has been reported with the Thr984Lys variant. 0.5pt

One homozygous individual, patient GT72, has been reported with the Thr984Lys variant. PubMed:25728920

PP3

Multiple lines of computational evidence support a deleterious effect with a REVEL score of 0.774 (above the >0.7 threshold).

PM2_Supporting

This variant is absent from gnomAD, ExAC and 1000 Genomes.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.