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_000212.3:c.1728del

CA915940253

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 12180185-5824-4aa1-9378-3110470434b7

Approved on: 2021-09-14

Published on: 2021-12-23

HGVS expressions

NM_000212.3:c.1728del

NC_000017.11:g.47299345del

CM000679.2:g.47299345del

NC_000017.10:g.45376711del

CM000679.1:g.45376711del

NC_000017.9:g.42731710del

NG_008332.2:g.50504del

ENST00000559488.7:c.1728del

ENST00000559488.5:c.1728del

ENST00000560629.1:n.1693del

NM_000212.2:c.1728del

Pathogenic

PP4_Strong PM3_Supporting PVS1 PM2_Supporting

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_000212.3(ITGB3):c.1728del variant results in a frameshift (p.Ser577ProfsTer92) with a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least two probands has been reported with this variant, including GT28 of PMID: 29675921 who meets the criteria for PP4_strong. GT28 is compound heterozygous for c.1728del and Gln298Ter (Classified Pathogenic by the PD-VCEP; PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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: PVS1, PM2_supporting, PM3_supporting, PP4_strong. (VCEP specifications version 2; date of approval xx/xx/xxxx)

PP4_Strong

GT28 of PMID: 29675921 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.

PM3_Supporting

GT28 of PMID: 29675921 is compound heterozygous for c.1728del and Gln298Ter (Classified Pathogenic by the PD-VCEP). Confirmation of trans phase was not reported. 0.5pt (PM3_supporting).

PVS1

The c.1728del variant results in a frameshift (p.p.Ser577ProfsTer92) with a premature stop codon in exon 12/15 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

PM2_Supporting

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

Curation History

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