Variant: NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp)

CA123228

13555 (ClinVar)

Gene: ITGB3

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: bf7df2fe-141e-481a-befc-3d870f5eab47

Approved on: 2024-08-20

Published on: 2024-08-20

HGVS expressions

NM_000212.2:c.718C>T
NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp)
NC_000017.11:g.47286363C>T
CM000679.2:g.47286363C>T
NC_000017.10:g.45363729C>T
CM000679.1:g.45363729C>T
NC_000017.9:g.42718728C>T
NG_008332.2:g.37522C>T
ENST00000696963.1:c.718C>T
ENST00000559488.7:c.718C>T
ENST00000559488.5:c.718C>T
ENST00000560629.1:c.683C>T
ENST00000571680.1:c.718C>T
NM_000212.3:c.718C>T

Likely Pathogenic

• Met criteria codes: PP3 PM5 PM3 PP4_Moderate PM2_Supporting

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000212.2(ITGB3):c.718C>T (p.Arg240Trp) missense variant has been reported in at least five patients (PMID: 32200672, 7509233, 1602006, doi.org/10.2491/jjsth.10.243, and a thesis by Zapelli in 2014) with a phenotype highly specific to GT. Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous (PM3) and meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population (PM2_supporting). It is predicted to have a deleterious effect (REVEL score 0.832; PP3) and occurs at the same residue as pathogenic variant Arg240Gln (PM5). In summary this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_Supporting, PM3, PM5, PP3, and PP4_Moderate.

Met criteria codes

• PP3: The REVEL score for this variant is 0.832, exceeding the VCEP-established threshold of >0.7 to support a deleterious effect.
• PM5: Arg240Trp occurs at the same residue as Arg240Gln (classified Pathogenic by the PD-VCEP).
• PM3: Three probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 are homozygous for Arg240Trp. A compound heterozygote has also been reported in https://doi.org/10.2491/jjsth.10.243 but is not considered here.
• PP4_Moderate: Several probands from PMID: 32200672, PMID: 7509233, and PMID: 1602006 meet the criteria for PP4_moderate; including mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin. Additionally, surface αIIbβ3 was dysfunctional as shown by defective PAC-1 and fibrinogen binding. Not reported if both ITGA2B and ITGB3 were fully sequenced in any of the patients.
• PM2_Supporting: This variant is at an extremely low frequency (below the <1/10,000 threshold) with a MAF of 0.00002196 (2/91,084 alleles) in the gnomADv4.1.0 South Asian population.