Variant: NM_000212.3:c.2031_2041del

CA915940605

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 7ee8b02a-62e1-4a04-8a76-56ad88a08791

Approved on: 2022-04-07

Published on: 2022-06-12

HGVS expressions

NM_000212.3:c.2031_2041del
NC_000017.11:g.47302737_47302747del
CM000679.2:g.47302737_47302747del
NC_000017.10:g.45380103_45380113del
CM000679.1:g.45380103_45380113del
NC_000017.9:g.42735102_42735112del
NG_008332.2:g.53896_53906del
ENST00000559488.7:c.2031_2041del
ENST00000559488.5:c.2031_2041del
ENST00000560629.1:n.1996_2006del
NM_000212.2:c.2031_2041del

Pathogenic

• Met criteria codes: PM3_Supporting PM2_Supporting PP4_Moderate PVS1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.3(ITGB3):c.2031_2041del in exon 13/15 is a frameshift variant creating p.(Asp677Glufs*4), where it is predicted to cause a premature stop codon and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This is thought to be a founder variant in the Iraqi-Jewish population and has been identified in at least 12 patients from 9 kindreds (PMID: 2014236). At least two patients (Patients 2 and 4 in PMID: 30078718) 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 absent as measured by flow cytometry. Patient 2 is homozygous for the variant (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, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 01/18/2022)

Met criteria codes

• PM3_Supporting: Patient 2 of PMID: 30078718 is homozygous for the variant (PM3_supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP4_Moderate: At least two patients (Patients 2 and 4 in PMID: 30078718) 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 absent as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries.
• PVS1: NM_000212.3(ITGB3):c.2031_2041del in exon 13/15 is a frameshift variant creating p.(Asp677Glufs*4), where it is predicted to cause a premature stop codon and lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).