NM_000212.3:c.724C>T

CA400023596

Gene: ITGB3

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: c89de113-f1ee-4763-b864-e97a20252268

Approved on: 2020-11-10

Published on: 2021-01-22

HGVS expressions

NM_000212.3:c.724C>T
NC_000017.11:g.47286369C>T
CM000679.2:g.47286369C>T
NC_000017.10:g.45363735C>T
CM000679.1:g.45363735C>T
NC_000017.9:g.42718734C>T
NG_008332.2:g.37528C>T
NM_000212.2:c.724C>T
ENST00000559488.5:c.724C>T
ENST00000560629.1:n.689C>T
ENST00000571680.1:c.724C>T

Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PVS1

• Not Met criteria codes: PM3

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Evidence submitted by expert panel

Platelet Disorders VCEP

NM_000212.3(ITGB3):c.724C>T (p.Arg242Ter) is a stop-gain (nonsense) variant that has been reported previously in at least one proband who satisfies the diagnostic criteria for the GT phenotype (PMID: 22250950). MAF of this variant for the Non-Finnish European subpopulation is 0.000064 in gnomAD v2.1.1. This nonsense variant is predicted to cause NMD and loss of function. This variant meets GT specific criteria for PVS1, PM2_Supporting and PP4_moderate and is therefore classified as Pathogenic.

Met criteria codes

• PP4_Moderate: Proband GT4 presented with mucocutaneous bleeding, showed a reduced expression of aIIbb3 expression (~10%) by flow cytometry and an absence of platelet aggregation to all physiological agonists except ristocetin. (PMID: 22250950) However, Since there is no information confirming full sequencing of ITGB3 and ITGA2B genes, PP4_Moderate is applied.
• PM2_Supporting: The overall AF in gnomAD v2.1.1 is 0.00003 (1/31396) and the MAF in the European (Non Finnish) subpopulation is 0.000064 (1/15426). This is below the recommended threshold of 0.01%.PM2_supporting applied.
• PVS1: This is a nonsense (stop-gain) variant located in exon 5 of 15 that is predicted to cause NMD and loss of function.

Not Met criteria codes

• PM3: This variant has been reported in compound heterozygosity with variant p.Cys624tyr (with phase unconfirmed), which has been classified as Pathogenic by ClinGen Platelet VCEP. (PMID:22250950) However, this evidence is not considered here to avoid circularity.