Variant: NM_000419.5:c.423G>T

CA399806022

1691484 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: dbf139ea-99d4-4741-aec7-223bc87d713a

Approved on: 2025-02-18

Published on: 2025-02-18

HGVS expressions

NM_000419.5:c.423G>T
NC_000017.11:g.44385702C>A
CM000679.2:g.44385702C>A
NC_000017.10:g.42463070C>A
CM000679.1:g.42463070C>A
NC_000017.9:g.39818596C>A
NG_008331.1:g.8804G>T
ENST00000262407.6:c.423G>T
ENST00000262407.5:c.423G>T
ENST00000592944.1:n.108G>T
NM_000419.3:c.423G>T
NM_000419.4:c.423G>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM3_Supporting PP4_Strong PP3

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

Evidence submitted by expert panel

Platelet Disorders VCEP

The missense variant NM_000419.5(ITGA2B):c.423G>T (p.Trp141Cys) has been reported in at least one patient (GT14 in PMID: 25728920), with mucocutaneous bleeding and impaired aggregation against 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). GT14 of PMID: 25728920 is compound heterozygous for Trp141Cys and c.2902del (classified as Pathogenic by the PD-EP), confirmation of trans phase was not reported (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.879, 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, PM3_supporting, PP3. (VCEP specifications version 2.1)

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• PM3_Supporting: GT14 of PMID: 25728920 is compound heterozygous for Trp141Cys and c.2902del (classified as Pathogenic by the PD-EP), confirmation of trans phase was not reported (0.5pt; PM3_supporting).
• PP4_Strong: At least one patient (GT14 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)
• PP3: The computational predictor REVEL gives a score of 0.879, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).