Variant: NM_000419.5:c.2390del

CA2573131754

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 7478da03-3e44-4631-9fbc-a72ab825838a

Approved on: 2022-09-20

Published on: 2022-12-07

HGVS expressions

NM_000419.5:c.2390del
NC_000017.11:g.44376144del
CM000679.2:g.44376144del
NC_000017.10:g.42453512del
CM000679.1:g.42453512del
NC_000017.9:g.39809038del
NG_008331.1:g.18363del
ENST00000262407.6:c.2390del
ENST00000648408.1:n.1821del
ENST00000262407.5:c.2390del
ENST00000587295.5:n.42del
ENST00000592462.5:n.1185del
NM_000419.3:c.2390del
NM_000419.4:c.2390del

Pathogenic

• Met criteria codes: PP4_Moderate PVS1 PM2_Supporting

• Not Met criteria codes: PM3

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_000419.5(ITGA2B):c.2390del (p.Gly797ValfsTer29) frameshift variant in exon 24 is predicted to cause a premature stop codon in biologically-relevant-exon 25/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Case 9 in PMID: 34066320) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). 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, PP4_moderate.

Met criteria codes

• PP4_Moderate: At least one patient (Case 9 in PMID: 34066320) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced, as measured by flow cytometry. However,ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.
• PVS1: The NM_000419.5(ITGA2B):c.2390del (p.Gly797ValfsTer29) frameshift variant in exon 24 is predicted to cause a premature stop codon in biologically-relevant-exon 25/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PM3: Case 9 (PMID: 34066320) is compound heterozygous for c.2390del and Gln778Pro (classified pathogenic by the PD-EP). The variants are reported to be in trans. Not considered here to avoid circularity.