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:c.2930del

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA915940386

953016 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8180aaec-e141-4303-8bb8-9ade936d675c

Approved on: 2020-09-06

Published on: 2021-08-20

HGVS expressions

NM_000419.5:c.2930del

NC_000017.11:g.44374672del

CM000679.2:g.44374672del

NC_000017.10:g.42452040del

CM000679.1:g.42452040del

NC_000017.9:g.39807566del

NG_008331.1:g.19834del

ENST00000262407.6:c.2930del

ENST00000648408.1:n.2361del

ENST00000262407.5:c.2930del

ENST00000587295.5:n.253+1161del

ENST00000588098.1:n.24del

ENST00000592462.5:n.2441del

NM_000419.3:c.2930del

NM_000419.4:c.2930del

Pathogenic

PVS1_Strong PP4_Strong PM2_Supporting 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 c.2930del variant has been reported in one compound heterozygous individual with phenotypes highly consistent with GT (PMID: 12083483). This frameshift variant occurs in exon 28 results in 63 altered amino acids followed by as stop loss and the elongation of the protein by 90 amino acids. The variant is absent from population databases including gnomAD, ExAC, and 1000 Genomes. In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PVS1_Strong, PM2_Supporting, PM3, and PP4_Moderate.

PVS1_Strong

The c.2930del variant occurs in exon 28 of 30 but does not generate a new stop codon prior to the original site. Instead it would result in 63 altered amino acids, starting from Arg977, followed by as stop loss and the elongation of the protein by 90 amino acids until a new stop codon is reached. This alters the entirety of the transmembrane domain which is critical to protein function (PMID: 25617834) as well as the cytoplasmic domain.

PP4_Strong

Patient DRP of PMID: 12083483 meets the criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

PM2_Supporting

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

PM3

PMID: 20819594 Patient is compound heterozygous for the paternal c.1545-1del variant (classified by the Platelet Disorders VCEP as Pathogenic) and maternal c.2930del variant. 1pt

Curation History

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