Variant: NM_000419.5:c.2930del

CA915940386

953016 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 8180aaec-e141-4303-8bb8-9ade936d675c

Approved on: 2020-09-06

Published on: 2021-08-20

HGVS expressions

NM_000419.5:c.2930del
NC_000017.11:g.44374672del
CM000679.2:g.44374672del
NC_000017.10:g.42452040del
CM000679.1:g.42452040del
NC_000017.9:g.39807566del
NG_008331.1:g.19834del
ENST00000262407.6:c.2930del
ENST00000648408.1:n.2361del
ENST00000262407.5:c.2930del
ENST00000587295.5:n.253+1161del
ENST00000588098.1:n.24del
ENST00000592462.5:n.2441del
NM_000419.3:c.2930del
NM_000419.4:c.2930del

Pathogenic

• Met criteria codes: PVS1_Strong PP4_Strong PM2_Supporting PM3

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.2930del variant has been reported in one compound heterozygous individual with phenotypes highly consistent with GT (PMID: 12083483). This frameshift variant occurs in exon 28 results in 63 altered amino acids followed by as stop loss and the elongation of the protein by 90 amino acids. The variant is absent from population databases including gnomAD, ExAC, and 1000 Genomes. In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PM3, and PP4_Moderate.

Met criteria codes

• PVS1_Strong: The c.2930del variant occurs in exon 28 of 30 but does not generate a new stop codon prior to the original site. Instead it would result in 63 altered amino acids, starting from Arg977, followed by as stop loss and the elongation of the protein by 90 amino acids until a new stop codon is reached. This alters the entirety of the transmembrane domain which is critical to protein function (PMID: 25617834) as well as the cytoplasmic domain.
• PP4_Strong: Patient DRP of PMID: 12083483 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 all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.
• PM3: PMID: 20819594 Patient is compound heterozygous for the paternal c.1545-1del variant (classified by the Platelet Disorders VCEP as Pathogenic) and maternal c.2930del variant. 1pt