Variant: NM_000419.4:c.2267+1G>T

CA399798124

953038 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 2e5ddb23-a6c4-4f24-aa47-eeeae5b0f6c4

HGVS expressions

NM_000419.4:c.2267+1G>T
NC_000017.11:g.44377008C>A
CM000679.2:g.44377008C>A
NC_000017.10:g.42454376C>A
CM000679.1:g.42454376C>A
NC_000017.9:g.39809902C>A
NG_008331.1:g.17498G>T
ENST00000262407.6:c.2267+1G>T
ENST00000648408.1:n.1698+1G>T
ENST00000262407.5:c.2267+1G>T
ENST00000592462.5:n.1062+1G>T
NM_000419.3:c.2267+1G>T
NM_000419.5:c.2267+1G>T
NM_000419.5(ITGA2B):c.2267+1G>T

Pathogenic

• Met criteria codes: PM2_Supporting PM3_Supporting PVS1 PP4_Strong

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000419.4:c.2267+1G>T is a canonical splice site variant that alters the donor site in intron 22. This is expected to result in aberrant splicing with skipping of exon 22 resulting in a frameshift with a premature stop codon in exon 24 which would lead to NMD (PVS1). It is absent from population databases (PM2_supporting). The variant is reported in 1 compound heterozygous individual with the Gln778Pro pathogenic variant in trans (PMID: 29675921; PM3_supporting). This patient has a phenotype highly specific to GT, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of aIIbß3 measured by flow cytometry (PP4_strong). In summary, this variant is classified as pathogenic. GT-specific criteria applied: PVS1, PM2_Supporting, PM3_Supporting, and PP4_Strong.

Met criteria codes

• PM2_Supporting: The c.2267G>T variant is absent from population databases and meets PM2.
• PM3_Supporting: The variant is reported in a compound heterozygous individual with the Pathogenic variant, Gln778Pro in trans, but phase not confirmed. 0.5pt
• PVS1: The c.2267+1G>T is a canonical splice site variant that alters the donor site in intron 22. This is expected to result in aberrant splicing with skipping of exon 22 resulting in a frameshift with a premature stop codon in exon 24 which would lead to NMD.
• PP4_Strong: Proband from PMID: 29675921 meets criteria for PP4_strong, including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of aIIbß3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

Approved on: 2022-12-01

Published on: 2022-12-07