Variant: NM_000212.3:c.674del

CA915940689

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 56b9e0f9-6006-46e9-ac46-da25eef57b13

Approved on: 2022-05-17

Published on: 2022-06-12

HGVS expressions

NM_000212.3:c.674del
NC_000017.11:g.47286319del
CM000679.2:g.47286319del
NC_000017.10:g.45363685del
CM000679.1:g.45363685del
NC_000017.9:g.42718684del
NG_008332.2:g.37478del
ENST00000559488.7:c.674del
ENST00000559488.5:c.674del
ENST00000560629.1:n.639del
ENST00000571680.1:c.674del
NM_000212.2:c.674del

Pathogenic

• Met criteria codes: PP4_Moderate PM3_Supporting PVS1 PM2_Supporting

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.3:c.674del (p.Gln225ArgfsTer2) variant in ITGB3 exon 5 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one proband with Glanzmann thrombasthenia. The reported proband (GT30, PMID: 19691478) was homozygous for the variant (PM3_Supporting). At least one patient (Patient GT30 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. 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_Moderate. (VCEP specifications version 2; date of approval 05/17/2022)

Met criteria codes

• PP4_Moderate: At least one patient (Patient GT30 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, αIIbβ3 surface expression was reduced to <5%, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.
• PM3_Supporting: This variant has been detected in at least one proband with Glanzmann thrombasthenia. The reported proband (GT30, PMID: 19691478) was homozygous for the variant (0.5 points). Total points: 0.5 (PM3_Supporting).
• PVS1: The c.674del (p.Gln225ArgfsTer2) variant in exon 5 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/15 and is predicted to lead 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).