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.3077G>A (p.Arg1026Gln)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA10575572

50232 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1ffdc596-436a-4da2-853f-c11978b6a47c

Approved on: 2023-09-07

Published on: 2023-09-21

HGVS expressions

NM_000419.5(ITGA2B):c.3077G>A

NM_000419.5:c.3077G>A

NM_000419.5(ITGA2B):c.3077G>A (p.Arg1026Gln)

NC_000017.11:g.44372407C>T

CM000679.2:g.44372407C>T

NC_000017.10:g.42449775C>T

CM000679.1:g.42449775C>T

NC_000017.9:g.39805301C>T

NG_008331.1:g.22099G>A

ENST00000262407.6:c.3077G>A

ENST00000648408.1:c.2391G>A

ENST00000262407.5:c.3077G>A

ENST00000587295.5:c.270G>A

ENST00000588098.1:c.54G>A

NM_000419.3:c.3077G>A

NM_000419.4:c.3077G>A

Uncertain Significance

PP3 PM3 PM2_Supporting

BS3 PS3 PP4 PM5

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.3077G>A variant results in the Arg1026Gln missense change. It is absent in population databases, including gnomADv2.1.1 (PM2_supporting), and is predicted damaging by in silico tools (REVEL score of 0.904; PP3). One compound heterozygous individual with mild bleeding, thrombocytopenia and platelet anisotrpy is reported in the literature several times (PMID: 25728920) with confirmation of c.1440-13_1440-1del (classified Pathogenic by the PD VCEP; PM3) in trans. The variant results in reduced expression of the αIIbβ3 complex on platelet surface. The expressed αIIbβ3 was not constitutively active and were able to bind fibrinogen only upon activation by anti-LIBS antibody. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PP3 (PD VCEP specifications version 2.1).

PP3

Arg1026Gln meets criteria for PP3 with a REVEL score of 0.904 (REVEL >0.7)

PM3

GT10/Paitent AP compound heterozygous for c.1440-13_1440-1del (classified Pathogenic by the Platelet Disorders VCEP) and Arg1026Gln with variants confirmed in trans. 1pt

PM2_Supporting

The Arg1026Gln variant is reported in gnomAD v2.1.1 at a frequency of 0.000008801 (1/113618 non-Finnish European alleles), meeting criteria for PM2 (MAF <0.0001)

BS3

Although the mutant αIIbβ3 complex was functional, as noted with PAC-1 binding upon activation, its expression was reduced by 50% compared to wild type. The evidence thus does not meet criteria for BS3

PS3

The expression of the αIIbβ3 complex evaluated by flow cytometry was 50% of that of wild-type in transfected COS-7 and CHO cell lines. PAC-1 binding was similar to wild-type αIIbβ3, when activated by anti-LIBS antibody, in CHO cells. The evidence does not meet criteria for PS3.

PP4

GT10 (aka patient AP) from PMID: 25728920 does not meet criteria for PP4. Although platelet expression was reduced (~12-50% of wild type), residual platelet aggregation with ADP is noted and Fg binding was evident upon stimulation. Patient also displayed modest thrombocytopenia (Platelet counts ranged between 100 and 160 × 109/L over a 10-year period) and platelet anisotropy. This individual has been reported in multiple publications (noted in additional comments with the PMID).

PM5

Arg1026Trp is a variant reported at the same residue, which has been reported in patients with autosomal dominant macrothrombocytopenia. It has been classified as a VUS in relation to GT by Platelet Disorders VCEP.

Curation History

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