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:c.1028T>C

CA399804619

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 027d3ed8-b21f-44dd-bba6-8d161a3cb738

Approved on: 2023-05-16

Published on: 2023-05-16

HGVS expressions

NM_000419.4:c.1028T>C

NC_000017.11:g.44383675A>G

CM000679.2:g.44383675A>G

NC_000017.10:g.42461043A>G

CM000679.1:g.42461043A>G

NC_000017.9:g.39816569A>G

NG_008331.1:g.10831T>C

ENST00000262407.6:c.1028T>C

ENST00000648408.1:n.459T>C

ENST00000262407.5:c.1028T>C

ENST00000592226.5:n.268T>C

NM_000419.3:c.1028T>C

NM_000419.5:c.1028T>C

Pathogenic

PP4_Strong PP3 PM3_Strong PM2_Supporting

BP2

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(ITGA2B):c.1028T>C variant results in the missense change, Leu343Pro. The variant is absent from population databases, including gnomADv2.1.1 (PM2_supporting). It is predicted damaging by in-silico tools (REVEL score of 0.838l; PP3). It is reported in at least 4 probands (PMIDs: 36672149, 19691478, 34267460), two homozygous and two compound heterozygous individuals, one of whom the variant was seen in trans with the pathogenic variant, Leu973AlafsTer63 (PM3_strong). Patient 3 (PMID: 34267460) 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 <25%, as measured by flow cytometry(PP4_strong). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_supporting, PP3, PM3_strong, PP4_strong (VCEP specifications version 2).

PP4_Strong

At least one patient (Patient 3 in PMID: 34267460) 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 <25%, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong)

PP3

REVEL score of 0.838, which is greater than or equal to 0.7; therefore, PP3 is met.

PM3_Strong

Patient GT18 from PMID: 19691478 is compound heterozygous for Leu343Pro and Leu973AlafsTer63 (classified "pathogenic" by ClinGen Platelet Disorders VCEP), confirmed in trans (1pt). Patients 2 and 3 from PMID: 34267460 are each homozygous (1pt) Total 2pt (PM3_strong).

PM2_Supporting

Absent from gnomAD v2.1.1 (PM2_supporting).

BP2

This variant (Leu343Pro) is in cis with the variant g.951G>A (PMID: 19691478); however, BP2 cannot be met because VUS g.951G>A is not known to be pathogenic.

Curation History

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