Variant: NM_000212.3:c.842A>C

CA400024802

1330335 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: ef63c97b-506b-488b-ae9e-6d8a57a0d655

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000212.3:c.842A>C
NC_000017.11:g.47287134A>C
CM000679.2:g.47287134A>C
NC_000017.10:g.45364500A>C
CM000679.1:g.45364500A>C
NC_000017.9:g.42719499A>C
NG_008332.2:g.38293A>C
ENST00000696963.1:c.842A>C
ENST00000559488.7:c.842A>C
ENST00000559488.5:c.842A>C
ENST00000560629.1:c.807A>C
ENST00000571680.1:c.842A>C
NM_000212.2:c.842A>C

Likely Pathogenic

• Met criteria codes: PM3_Supporting PP4_Strong PM2_Supporting 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 NM_000212.3(ITGB3):c.842A>C (p.His281Pro) missense variant has been identified in at least 1 probands, GT11 of PMID: 29675921 meeting the criteria for PP4_strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. GT11 of PMID: 29675921 is compound heterozygous for His281Pro and Cys400Tyr (classified Pathogenic by the PD-VCEP; PM3_Supporting) without confirmation of phasing . This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.988, which predicts a damaging effect on ITGB3 function (PP3). In summary, this variant meets the 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: PM2_supporting, PP3, PP4_strong, PM3_supporting. (VCEP specifications version 2; date of approval xx/xx/xxxx)

Met criteria codes

• PM3_Supporting: GT11 of PMID: 29675921 is compound heterozygous for His281Pro and Cys400Tyr (Classified Pathogenic by the PD-VCEP). Confirmation of trans phase was not reported. 0.5pt (PM3_Supporting)
• PP4_Strong: GT11 of PMID: 29675921 meets the criteria for PP4_strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.988, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on ITGB3 function (PP3).