Variant: NM_000212.3(ITGB3):c.1641C>A (p.Cys547Ter)

CA400030168

977131 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 08d055ef-9deb-4c6a-bd3b-7d6bc0b854f4

HGVS expressions

NM_000212.3:c.1641C>A
NM_000212.3(ITGB3):c.1641C>A (p.Cys547Ter)
NC_000017.11:g.47292519C>A
CM000679.2:g.47292519C>A
NC_000017.10:g.45369885C>A
CM000679.1:g.45369885C>A
NC_000017.9:g.42724884C>A
NG_008332.2:g.43678C>A
ENST00000559488.7:c.1641C>A
ENST00000559488.5:c.1641C>A
ENST00000560629.1:n.1606C>A
NM_000212.2:c.1641C>A

Pathogenic

• Met criteria codes: PP4_Strong PM3_Supporting PM2_Supporting PVS1

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.1641C>A (p.Cys547Ter) variant in exon 10/15 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It has been reported homozygous (PM3_supporting) in at least one GT proband (P18 in PMID: 34275420) who displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was absent, as measured by flow cytometry (PP4_strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PM3_supporting, PP4_strong.

Met criteria codes

• PP4_Strong: At least one patient (P18 in PMID: 34275420) 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_Supporting: P18 is homozygous for this variant (PMID: 34275420; PM3_supporting)
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PVS1: The c.1641C>A (p.Cys547Ter) variant in exon 10/15 is a nonsense variant predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Approved on: 2022-09-20

Published on: 2022-12-07