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.409-2_419del

CA10575471

2889 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4d6a641c-0498-4bd3-8eb1-854be8a92082

HGVS expressions

NM_000419.5:c.409-2_419del

NM_000419.5(ITGA2B):c.409-2_419del

NC_000017.11:g.44385708_44385720del

CM000679.2:g.44385708_44385720del

NC_000017.10:g.42463076_42463088del

CM000679.1:g.42463076_42463088del

NC_000017.9:g.39818602_39818614del

NG_008331.1:g.8788_8800del

ENST00000262407.6:c.409-2_419del

ENST00000262407.5:c.409-2_419del

ENST00000592944.1:n.92_104del

NM_000419.3:c.409-2_419del

NM_000419.4:c.409-2_419del

Pathogenic

PM2_Supporting PVS1_Strong PP4_Strong PS3 PM3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.409-2_419del variant was first reported in the Palestinian population by PMID: 2014236; haplotype analysis in PMID: 16359514 is consistent with a founder effect. This variant has also been described as c.409-3_418del and HGVS nomenclature is c.409-4_417del. The deletion causes use of a cryptic splice site at position c.425_426 (confirmed in patient mRNA in PMID: 2014236). As such there is an in-frame deletion of 18bp encompassing 6 amino acids (Ala137 through Gln142) in the critical ligand binding beta-propeller domain. This variant is absent from all population databases, including gnomAD. The variant has been identified homozygous in at least 8 patients (PMIDs: 2014236, 16359514). with a phenotype highly specific to GT. Transfection in BHK cells resulted in lack of surface expression of αIIbβ3 (PMID: 16359514). In summary this variant is classified as Pathogenic for GT. GT-specific criteria applied: PVS1_strong, PS3, PM2_supporting, PM3, PP4_strong.

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PVS1_Strong

The canonical splice variant is predicted to result in the skipping of exon 4 of 30, causing a frameshift with a premature stop codon in the next exon which is predicted to result to in NMD. However, splicing predictors, including spliceAI (score 0.91), predict gain of an acceptor site and it has been reported in the literature that there is use of a cryptic splice site at position c.425_426 (confirmed in patient mRNA in PMID: 2014236). As such there is an in-frame deletion of 18bp encompassing 6 amino acids (Ala137 through Gln142). This deletion occurs in the critical ligand binding beta-propeller domain.

PP4_Strong

Eight patients from PMID: 16359514 meet the 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.

PS3

Flow cytometric analysis of αIIbβ3 surface expression was performed in transfected baby hamster kidney cells, with normal β3 cDNA and either normal αIIb cDNA or mutated cDNA with the 13-bp deletion. This demonstrated lack of surface expression of αIIbβ3 in cells transfected with the 13-bp deletion. Furthermore, immunoblot analysis using an antibody against αIIb (SZ22) showed no αIIb in cells containing the 13-bp deletion.

PM3

Eight patients from PMID: 16359514 meet the maximum of 1pt for homozygous occurrences.

Approved on: 2021-05-07

Published on: 2021-08-20

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