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]

Variant: NM_000419.4(ITGA2B):c.1878G>C (p.Gln626His)

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CA115852

2903 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 57f0837e-2d71-4368-b20e-a9445687d83d

Approved on: 2020-09-04

Published on: 2021-08-20

HGVS expressions

NM_000419.4:c.1878G>C

NM_000419.4(ITGA2B):c.1878G>C (p.Gln626His)

ENST00000262407.6:c.1878G>C

ENST00000648408.1:n.1309G>C

ENST00000262407.5:c.1878G>C

ENST00000592462.5:n.673G>C

NM_000419.3:c.1878G>C

NM_000419.5:c.1878G>C

NC_000017.11:g.44379689C>G

CM000679.2:g.44379689C>G

NC_000017.10:g.42457057C>G

CM000679.1:g.42457057C>G

NC_000017.9:g.39812583C>G

NG_008331.1:g.14817G>C

Pathogenic

PM2_Supporting PP4_Strong PM4 PM3 PP1 PP3

PS3

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The c.1878G>C; p.Gln626His splicing variant has been reported in at least 5 GT probands (PMIDs: 20020534, 22513797, 25728920, 21113249, 29474205) and co-segregated in one additional affected family member (PMID: 22513797). It is absent from ExAC and gnomAD. Flow cytometric studies of the mutant protein expressed in COS-7 cells showed that the mutation did not prevent expression of the GPIIb/IIIa complex on the cell surface (PMID: 20020534). However, the mutation was found to result in a splice site error, skipping of exon 18, which could explain the absence of mRNA in the patients (PMID: 20020534). Splicing predictors, HSF and MaxEntScan, agree that there is alteration to the WT donor site, most likely affecting splicing. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM4, PP3, PP4_Strong, and PP1.

PM2_Supporting

The c.1878G>C variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PP4_Strong

Five probands have been described in the literature at least one of whom (PMID: 25728920) meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

PM4

Study of the patient’s platelet mRNA revealed full normal beta-3 mRNA synthesis but alpha-IIb mRNA remained undetectable. The c.1878G>C variant affects the wild type donor site of intron 18 and the mutation was found to result in a splice site error, in the form of skipping of exon 18 (confirmed by minigene study in PMID: 20020534). Exon 18 skipping preserves the reading frame and removes less than 10% of the protein.

PM3

At least four probands have been described homozygous for the c.1878G>C variant.

PP1

Co-segregation of homozygous c.1878G>C with disease was observed in the proband and one affected sibling (PMID: 22513797).

PP3

Human Splicing Finder (-12.28% variation) and MaxEntScan (-67.02% variation) agree that there is alteration of the WT donor site, most probably affecting splicing.

PS3

This c.1878G>C variant does not prevent the expression of the mutant complex at the surface of transfected COS-7 cells but protein function was not assessed (PMID: 20020534).

Curation History

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