Variant: NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp)

CA115837

2894 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 315ee6aa-c6dd-4c98-97b1-5c49fedfb665

Approved on: 2021-03-05

Published on: 2021-08-20

HGVS expressions

NM_000419.5:c.818G>A
NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp)
NC_000017.11:g.44384567C>T
CM000679.2:g.44384567C>T
NC_000017.10:g.42461935C>T
CM000679.1:g.42461935C>T
NC_000017.9:g.39817461C>T
NG_008331.1:g.9939G>A
ENST00000262407.6:c.818G>A
ENST00000648408.1:c.249G>A
ENST00000262407.5:c.818G>A
ENST00000589645.5:n.269G>A
ENST00000591990.5:n.180G>A
ENST00000592075.5:n.187G>A
ENST00000592226.5:n.58G>A
ENST00000592253.5:n.326G>A
ENST00000592944.1:n.500G>A
NM_000419.3:c.818G>A
NM_000419.4:c.818G>A

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PP3 PM3_Supporting PS3_Moderate

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.818G>A (p.Gly273Asp) variant has been reported, in the homozygous state, in at least one proband (PMID: 8282784) with a GT-specific phenotype. It is absent from population databases, including gnomAD and is predicted deleterious (REVEL score 0.845). 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 Gly273Asp 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 Gly273Asp. PMID: 8916916 reports similar immunoprecipitation results. 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, PM2_supporting, PM3_supporting, PP3, and PP4_moderate.

Met criteria codes

• PP4_Moderate: The patient in PMID: 8282784 meets the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, the patient had <5% expression by flow cytometry. The same individual was reported as GTP2 in PMID: 24335497, with no additional phenotypic information.
• PM2_Supporting: This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.
• PP3: The REVEL score for this variant is 0.845, exceeding the VCEP-established threshold of >0.7 to support a deleterious effect.
• PM3_Supporting: The patient from PMID: 8282784 is homozygous for Gly273Asp.
• 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 Gly273Asp 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 Gly273Asp. PMID: 8916916 reports similar immunoprecipitation results. These results were considered sufficient evidence of impaired surface expression for application of the PS3_moderate criteria.