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.1063G>A (p.Glu355Lys)

CA115844

2899 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

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

PM2_Supporting PS3 PP3 PP4_Moderate PM3

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.

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.

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.

PP3

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

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.

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.

Approved on: 2021-02-10

Published on: 2021-08-20

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