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_000419.5(ITGA2B):c.1063G>A (p.Glu355Lys)

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CA115844

2899 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4fb9bbea-ef5f-4224-a74d-fbf5b546f159

Approved on: 2021-02-10

Published on: 2021-08-20

HGVS expressions

NM_000419.5:c.1063G>A

NM_000419.5(ITGA2B):c.1063G>A (p.Glu355Lys)

NC_000017.11:g.44383640C>T

CM000679.2:g.44383640C>T

NC_000017.10:g.42461008C>T

CM000679.1:g.42461008C>T

NC_000017.9:g.39816534C>T

NG_008331.1:g.10866G>A

ENST00000262407.6:c.1063G>A

ENST00000648408.1:n.494G>A

ENST00000262407.5:c.1063G>A

ENST00000592226.5:n.303G>A

NM_000419.3:c.1063G>A

NM_000419.4:c.1063G>A

Pathogenic

PS3 PM2_Supporting PP3 PM3 PP4_Moderate

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 NM_000419.5(ITGA2B):c.1063G>A (p.Glu355Lys) missense variant has been reported in several patients (PMIDs: 11122161, 9722314, 9215749, 22250950, 9734640) with a phenotype highly specific to GT. It is occurs at a very low allele frequency of 0.00001978 (2/101,102 alleles) in the non-Finnish European gnomAD population. The variant is predicted to have a deleterious effect (REVEL score 0.793). The functional impact has been assessed by transfection in CHO cells, showing lack of αIIbβ3 surface expression with the Glu355Lys mutant (PMIDs: 11122161, 12362239). In summary this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS3, PM2_Supporting, PM3, PP3, and PP4_Moderate.

PS3

In PMID: 11122161 and PMID: 12362239, surface expression, in transfected CHO cells expressing normal β3, was measured by flow cytometry, finding that the Glu355Lys variant prevented the surface expression of the αIIbβ3.

PM2_Supporting

This variant is at an extremely low frequency (below the <1/10,000 threshold) with an overall allele frequency from gnomAD of 0.000008807 and MAF of 0.00001978 (2/101,102 alleles) in the non-Finnish European population.

PP3

REVEL score of 0.793 is above the >.0.7 threshold, in support of a deleterious effect.

PM3

At least four homozygous patients have been reported (PMIDs: 11122161, 9722314, 9215749, 22250950) for Glu355Lys. An additional compound heterozygous case has been reported (in PMID: 9734640) with Ile596Thr, which is not considered here as Ile596Thr has an allele frequency above the threshold for PM2.

PP4_Moderate

The patient in PMID: 11122161 meets criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, there was an absence of platelet GPIIb, as measured by flow cytometry and Western blot.

Curation History

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