Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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

CA8603160

2898 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM2_Supporting PM4 PP4_Moderate PS3_Moderate

PM3

Evidence Links 1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

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.

PM2_Supporting

This variant is absent from gnomAD v4.0.0 (PM2_Supporting).

PM4

The Val456_Asp457del variant causes an in-frame deletion of two amino acids.

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.

Introduced the deletion into the sequence of a wild-type αIIb cDNA and expressed the αIIb mutant in COS-1 cells, either alone or with wild-type β3. Deletion of Val425 and Asp426 did not impair αIIb synthesis, nor did it impair heterodimer assembly however the αIIb mutant remained in the pro-αIIb form. To confirm that deletion prevents the transport of αIIbβ3 to the cell surface, the cell surface was with 125I and immunoprecipitated using polyclonal anti-αIIb antisera. Labeled complexes were present on the surface of cells expressing wild-type αIIbβ3, but were not present on surface of cells expressing β3 and the αIIb mutant. Neither Western blot or flow cytometry was performed. PubMed:8704171

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.

Approved on: 2024-04-16

Published on: 2024-04-16

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