Variant: NM_000419.4:c.2602-2A>G

CA399793915

1210193 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: b631b1d7-7591-4c2c-bf24-b2ae259d1b9e

Approved on: 2023-09-07

Published on: 2023-09-21

HGVS expressions

NM_000419.4:c.2602-2A>G
NC_000017.11:g.44375718T>C
CM000679.2:g.44375718T>C
NC_000017.10:g.42453086T>C
CM000679.1:g.42453086T>C
NC_000017.9:g.39808612T>C
NG_008331.1:g.18788A>G
ENST00000262407.6:c.2602-2A>G
ENST00000648408.1:c.2033-2A>G
ENST00000262407.5:c.2602-2A>G
ENST00000587295.5:c.253+115A>G
ENST00000592462.5:n.1397-2A>G
NM_000419.3:c.2602-2A>G
NM_000419.5:c.2602-2A>G
NM_000419.5(ITGA2B):c.2602-2A>G

Likely Pathogenic

• Met criteria codes: PP4_Strong PVS1_Moderate PM2_Supporting

• Not Met criteria codes: PM3 BP2

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.2602-2A>G variant disrupts the canonical splice acceptor site in intron 25 and is predicted to result in skipping of exon 26, removing 3.9% of the protein (PVS1_moderate). The variant is absent from population database, including gnomADv2.1.1 (PM2_supporting). It is reported in one compound heterozygous individual with the c.2602-3C>A and Thr281Ile (PMID: 25373348). GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced (PP4_strong). In summary, based on evidence at this time the variant is classified as likely pathogenic for GT. GT-specific criteria applied: PVS1_Moderate, PP4_Strong, PM2_Supporting.

Met criteria codes

• PP4_Strong: GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced.
• PVS1_Moderate: The impact of this variant in the canonical splice acceptor site of intron 25 is not clear. It may lead to the skipping of exon 26 (in-frame, 42 amino acids, <10% of the protein), and hence, per SVI guidance, PVS1 at the lowest strength is applied.
• PM2_Supporting: The variant is absent from population databases, including gnomAD, and meets PM2.

Not Met criteria codes

• PM3: Patient GT16 is compound heterozygous for c.2602-2A>G/c.2602-3C>A and Thr281Ile (classified likely pathogenic by the PD-EP) in PMID: 25373348 but not considered here to avoid circularity.
• BP2: In PMID: 25373348 c.2602-2A>G was reported as occurring "together with" c.2602-3C>A (classified VUS by the Platelet Disorders VCEP), however the cis/trans relationship was not confirmed.