Variant: NM_000419.5(ITGA2B):c.1366_1371del (p.Val456_Asp457del)

CA8603160

2898 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 33b730a2-d6e5-4314-8f26-52dface31893

Approved on: 2024-04-16

Published on: 2024-04-16

HGVS expressions

NM_000419.5:c.1366_1371del
NM_000419.5(ITGA2B):c.1366_1371del (p.Val456_Asp457del)
NC_000017.11:g.44380902_44380907del
CM000679.2:g.44380902_44380907del
NC_000017.10:g.42458270_42458275del
CM000679.1:g.42458270_42458275del
NC_000017.9:g.39813796_39813801del
NG_008331.1:g.13600_13605del
ENST00000262407.6:c.1366_1371del
ENST00000648408.1:c.797_802del
ENST00000262407.5:c.1366_1371del
ENST00000592226.5:n.606_611del
ENST00000592462.5:n.161_166del
NM_000419.3:c.1366_1371del
NM_000419.4:c.1366_1371del

Likely Pathogenic

• Met criteria codes: PM4 PM2_Supporting PP4_Moderate PS3_Moderate

• 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.1366_1371del (p.Val456_Asp457del) variant causes an in-frame deletion of two amino acids (PM4). It has been reported, in at least one GT proband (PMID: 8704171). Patient LeM of PMID: 8704171 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, there was reduced surface expression of aIIbß3 measured by flow cytometry. This variant is absent from gnomAD v4.0.0 (PM2_Supporting). Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID: 8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Val456_Asp457del ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Val456_Asp457del ITGA2B. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria. In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PS3_moderate,PP4_Moderate, PM4, and PM2_supporting.

Met criteria codes

• PM4: The Val456_Asp457del variant causes an in-frame deletion of two amino acids.
• PM2_Supporting: This variant is absent from gnomAD v4.0.0 (PM2_Supporting).
• PP4_Moderate: Patient LeM of PMID: 8704171 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, there was reduced surface expression of aIIbß3 measured by flow cytometry. ITGA2B and ITGB3 were not fully sequenced across all exons and intron/exon boundaries.
• PS3_Moderate: Heterologous expression followed by the preferred assays, of either Western blot or flow cytometry, has not been reported for this variant. However in PMID: 8282784, to test for mutant complexes on the cell surface, COS-1 cells were cotransfected with WT ITGB3 and Val456_Asp457del ITGA2B, cells were surface labeled with 125I and immunoprecipitated, then labeled heterodimers were detected on the surface of cotransfected cells containing wildtype ITGA2B but not on the surface of cells containing Val456_Asp457del ITGA2B. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria.

Not Met criteria codes

• PM3: Val425_Asp426edl was the only variant noted in the patient from PMID: 8704171, it was inherited from the father. Studies to identify the mutant maternal allele were ongoing but the mother was noted to have 50% of the normal amount of αIIbβ3.