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.2883del (p.Phe961fs)

CA915940799

627052 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ebadcd3f-47eb-4264-b505-2be56efa733b

HGVS expressions

NM_000419.5:c.2883del

NM_000419.5(ITGA2B):c.2883del (p.Phe961fs)

NC_000017.11:g.44374719del

CM000679.2:g.44374719del

NC_000017.10:g.42452087del

CM000679.1:g.42452087del

NC_000017.9:g.39807613del

NG_008331.1:g.19787del

ENST00000262407.6:c.2883del

ENST00000648408.1:n.2314del

ENST00000262407.5:c.2883del

ENST00000587295.5:n.253+1114del

ENST00000592462.5:n.2394del

NM_000419.3:c.2883del

NM_000419.4:c.2883del

Pathogenic

PP4_Strong PM3_Supporting PM2_Supporting PVS1_Strong

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.2883del variant that results in the p.Phe961LeufsTer? frameshift has been reported homozygous in at least one GT patient (PMID: 22190468) with a highly specific phenotype. The variant causes stop loss and the addition of 90 amino acids to the ITGA2B protein, which alters the transmembrane domain. The variant is absent from population databases. In summary, based on the available evidence at this time, the variant is classified as pathogenic for GT. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PM3_supporting, PP4_Strong.

PP4_Strong

For patient TGP0086 (PMID: 31064749) the ClinVar submission SCV000899651.1 reports this individual to be affected with Glanzmann thrombasthenia. Personal communication with authors indicated that patient had diverse bleeding symptoms (epistaxis, bleeding after dental extraction, gastrointestinal bleeding) and impaired platelet aggregation (absent for ADP, Collagen, arachidonic acid, TRAP and U46 but there was response to ristocetin, which was reversible). FACS showed <5% expression of β3. Sequencing included coverage of all ITGA2B and ITGB3 exons and intron/exon boundaries.

PM3_Supporting

Patient TGP0086 (PMID: 31064749) is homozygous for this variant.

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PVS1_Strong

The c.2883del variant causes a frameshift and subsequent stop loss, p.Phe961LeufsTer?. This results in alteration of the remaining 79 amino acids followed by the addition of 90 amino acids to the ITGA2B protein. This alters the transmembrane domain of the protein which is considered a critical region for protein function by the Platelet Disorders VCEP. Per the SVI PVS1 decision tree, PVS1_Strong is applied.

Approved on: 2021-07-08

Published on: 2021-08-19

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