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.892C>T

CA400025098

Gene: ITGB3 (HGNC:3690)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: b69cc91a-b563-41d5-a9a7-da4f9b6f7e07

Approved on: 2021-06-30

Published on: 2021-12-23

HGVS expressions

NM_000212.3:c.892C>T

NC_000017.11:g.47287184C>T

CM000679.2:g.47287184C>T

NC_000017.10:g.45364550C>T

CM000679.1:g.45364550C>T

NC_000017.9:g.42719549C>T

NG_008332.2:g.38343C>T

ENST00000559488.7:c.892C>T

ENST00000559488.5:c.892C>T

ENST00000560629.1:n.857C>T

ENST00000571680.1:c.892C>T

NM_000212.2:c.892C>T

Pathogenic

PM3_Supporting PP4_Strong PM2_Supporting PVS1

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.892C>T (p.Gln298Ter) nonsense variant creates a premature stop codon in exon 6/15 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. A second patient in PMID: 21136216 is homozygous for Gln298Ter (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)

PM3_Supporting

PMID: 21136216 Patient is homozygous for Gln298Ter (reported as 892C>T Arg272Ter but sequence trace in Figure 1 confirms it is Gln272Ter, legacy for Gln298Ter). 0.5pt (PM3_supporting). GT28 is compound heterozygous for Gln298Ter and c.1728del (Classified Pathogenic by the PD-VCEP). Confirmation of trans phase was not reported. Not considered here to avoid circularity.

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.

PM2_Supporting

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

PVS1

The NM_000212.3(ITGB3):c.892C>T (p.Gln298Ter) is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 6/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Curation History

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