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:c.2933G>T

CA399790478

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 76f14c4b-2f06-4db0-987a-856a3058086f

Approved on: 2023-04-06

Published on: 2023-04-07

HGVS expressions

NM_000419.5:c.2933G>T

NC_000017.11:g.44374669C>A

CM000679.2:g.44374669C>A

NC_000017.10:g.42452037C>A

CM000679.1:g.42452037C>A

NC_000017.9:g.39807563C>A

NG_008331.1:g.19837G>T

ENST00000262407.6:c.2933G>T

ENST00000648408.1:n.2364G>T

ENST00000262407.5:c.2933G>T

ENST00000587295.5:n.253+1164G>T

ENST00000588098.1:n.27G>T

ENST00000592462.5:n.2444G>T

NM_000419.3:c.2933G>T

NM_000419.4:c.2933G>T

Uncertain Significance

PM2_Supporting PP4_Moderate PM3_Supporting

BP4 PS3 PP3

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:c.2933G>T (p.Gly978Val) variant in ITGA2B is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 978 (p.Gly978Val). At least one patient (Patient GT-1 in PMIDs 22837472 and 30934104) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, αIIbβ3 surface expression was reduced to 0%, as measured by flow cytometry. This individual was compound heterozygous for this variant and the NM_000419.5(ITGA2B):c.2994G>A (p.Trp998Ter) variant, which was classified as Pathogenic by the PD VCEP. The phase of the variants in this proband is unknown (PMID: 22837472, PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting (VCEP specifications version 2).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

At least one patient (Patient GT-1 in PMIDs 22837472 and 30934104) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 0% (<25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate)

PM3_Supporting

This variant has been detected in at least 1 proband with Glanzmann thrombasthenia. This individual was compound heterozygous for this variant and the NM_000419.5(ITGA2B):c.2994G>A (p.Trp998Ter) variant, which was classified as Pathogenic by the PD VCEP. The phase of the variants in this proband is unknown (0.5 PM3 points, PMID: 22837472, PM3_Supporting).

BP4

REVEL is not < 0.25. (REVEL = 0.379)

PS3

Experiments from PMID: 22837472 were done in patient cells, not a heterologous cell line.

PP3

REVEL is not > 0.7. (REVEL = 0.379)

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