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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000212.3:c.756del

CA923726221

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7d103fd0-f9f9-4429-a42e-b93d0ec446c2

HGVS expressions

NM_000212.3:c.756del

NC_000017.11:g.47286401del

CM000679.2:g.47286401del

NC_000017.10:g.45363767del

CM000679.1:g.45363767del

NC_000017.9:g.42718766del

NG_008332.2:g.37560del

ENST00000559488.7:c.756del

ENST00000559488.5:c.756del

ENST00000560629.1:n.721del

ENST00000571680.1:c.756del

NM_000212.2:c.756del

Pathogenic

PM3_Supporting PP4_Moderate 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

NM_000212.3(ITGB3):c.756del (p.Met253CysfsTer30) in exon 5 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 6/15 and is predicted to lead to nonsense mediated decay (PVS1). GT1 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 1.2%, as measured by flow cytometry. This variant is absent from gnomAD v2.1.1 (PM2_Supporting; PM3_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, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021)

PM3_Supporting

GT1 of PMID: 32237906 is homozygous for c.756del (0.5pt)

PP4_Moderate

GT1 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 1.2% (<25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.

PM2_Supporting

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

PVS1

The c.756del (p.Met253CysfsTer30) variant in exon 5 of ITGB3 is a frameshift 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).

Approved on: 2021-11-04

Published on: 2021-12-23

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