ITGA2B p.Phe320Ser

The NM_000419.5(ITGA2B):c.959T>C variant in ITGA2B is a missense variant predicted to cause substitution of Phenylalanine by Serine at amino acid 320 (p.Phe320Ser). At least one patient (Patient 1 in PMID: 9722314) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5% of normal, as measured by flow cytometry (PP4_Moderate). Surface expression of αIIbβ3 measured by flow cytometry in CHO cells transiently co-transfected with c.959T>C (p.Phe320Ser) variant αIIb and wild type β3 showed decreased expression at 3% WT levels, indicating that this variant impacts protein function (PMID: 9722314)(PS3). The computational predictor REVEL gives a score of 0.885, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). The highest population minor allele frequency in gnomAD v4.1 is 0.00002229 (1/44868 alleles) in the East Asian genetic ancestry group, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 2).