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_000419.4:c.2602-2A>G

CA399793915

1210193 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b631b1d7-7591-4c2c-bf24-b2ae259d1b9e

Approved on: 2023-09-07

Published on: 2023-09-21

HGVS expressions

NM_000419.4:c.2602-2A>G

NC_000017.11:g.44375718T>C

CM000679.2:g.44375718T>C

NC_000017.10:g.42453086T>C

CM000679.1:g.42453086T>C

NC_000017.9:g.39808612T>C

NG_008331.1:g.18788A>G

ENST00000262407.6:c.2602-2A>G

ENST00000648408.1:c.2033-2A>G

ENST00000262407.5:c.2602-2A>G

ENST00000587295.5:c.253+115A>G

ENST00000592462.5:n.1397-2A>G

NM_000419.3:c.2602-2A>G

NM_000419.5:c.2602-2A>G

NM_000419.5(ITGA2B):c.2602-2A>G

Likely Pathogenic

PVS1_Moderate PM2_Supporting PP4_Strong

PM3 BP2

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.2602-2A>G variant disrupts the canonical splice acceptor site in intron 25 and is predicted to result in skipping of exon 26, removing 3.9% of the protein (PVS1_moderate). The variant is absent from population database, including gnomADv2.1.1 (PM2_supporting). It is reported in one compound heterozygous individual with the c.2602-3C>A and Thr281Ile (PMID: 25373348). GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced (PP4_strong). In summary, based on evidence at this time the variant is classified as likely pathogenic for GT. GT-specific criteria applied: PVS1_Moderate, PP4_Strong, PM2_Supporting.

PVS1_Moderate

The impact of this variant in the canonical splice acceptor site of intron 25 is not clear. It may lead to the skipping of exon 26 (in-frame, 42 amino acids, <10% of the protein), and hence, per SVI guidance, PVS1 at the lowest strength is applied.

PM2_Supporting

The variant is absent from population databases, including gnomAD, and meets PM2.

PP4_Strong

GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced.

PM3

Patient GT16 is compound heterozygous for c.2602-2A>G/c.2602-3C>A and Thr281Ile (classified likely pathogenic by the PD-EP) in PMID: 25373348 but not considered here to avoid circularity.

BP2

In PMID: 25373348 c.2602-2A>G was reported as occurring "together with" c.2602-3C>A (classified VUS by the Platelet Disorders VCEP), however the cis/trans relationship was not confirmed.

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