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Submissions for variant NM_000419.5(ITGA2B):c.575-1_575insGGACAA (p.Phe191_Ser192insArgThr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV003330345 SCV004037417 pathogenic Glanzmann thrombasthenia 2023-09-07 reviewed by expert panel curation The NM_000419.5(ITGA2B):c.575_576insGACAAG (p.Phe191_Ser192insArgThr) variant is predicted to cause a change in the length of the protein due to an in-frame insertion of two amino acids in a non-repeat region (PM4). At least one patient (Patient KO in PMID: 9739052) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). The patient's platelets had normal amounts of surface alphaIIb and beta3 but failed to bind the ligand mimetic, IIb3-specific mAb, OP-G2. This patient was homozygous for the variant (PM3_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in 293 cells transiently co-transfected with the c.575_576insGACAAG (p.Phe191_Ser192insArgThr) variant αIIb and wild type β3 had normal surface expression but showed minimal binding (0%) to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 9739052)(PS3). 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: PS3, PP4_Moderate, PM4, PM2_Supporting, and PM3_Supporting (VCEP specifications version 2).

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