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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000419.5:c.1259T>C

CA399803733

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 678f59c9-6171-481a-90c0-bd5d5a13b35e

Approved on: 2022-06-02

Published on: 2022-06-12

HGVS expressions

NM_000419.5:c.1259T>C

NC_000017.11:g.44381013A>G

CM000679.2:g.44381013A>G

NC_000017.10:g.42458381A>G

CM000679.1:g.42458381A>G

NC_000017.9:g.39813907A>G

NG_008331.1:g.13493T>C

ENST00000262407.6:c.1259T>C

ENST00000648408.1:n.690T>C

ENST00000262407.5:c.1259T>C

ENST00000592226.5:n.499T>C

ENST00000592462.5:n.54T>C

NM_000419.3:c.1259T>C

NM_000419.4:c.1259T>C

Likely Pathogenic

PP3 PM2_Supporting PP4_Strong

PM3

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 NM_000419.5(ITGA2B):c.1259T>C (p.Val420Ala) missense variant has been reported in at least one patient (GT22 in PMID: 25728920) 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 (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PP3. (VCEP specifications version 2.1)

PP3

The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4_Strong

At least one patient (GT22 in PMID: 25728920) 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)

PM3

GT22 (PMID: 25728920) is compound heterozygous for Val420Ala and c.408+11C>A. Confirmation of trans phase was not reported. Not considered here to avoid cirucularity.

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.