Submissions for variant NM_000419.5(ITGA2B):c.520T>C (p.Tyr174His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003222576	SCV003916001	likely pathogenic	Glanzmann thrombasthenia	2023-04-06	reviewed by expert panel	curation	The NM_000419.5:c.520T>C variant in ITGA2B is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 174 (p.Tyr174His). At least one patient (Patient Osaka-12 in PMID: 12506038) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, patient platelets expressed 36%-41% αIIbβ3 but failed to bind soluble ligands, including a high-affinity αIIbβ3-specific peptidomimetic antagonist (OP-G2 and PAC-1). The computational predictor REVEL gives a score of 0.815, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). An expression vector that contained the wild-type or mutant His174 form of αIIb was cotransfected with a wild-type β3 vector into 293 cells. Flow cytometric analysis using FITC-AP3 or FITC-TP80 mAb showed that the expression levels of Tyr174HisαIIbβ3 were essentially the same as wild-type αIIbβ3. In sharp contrast, Tyr174HisαIIbβ3 failed to bind OP-G2 mAb, FITC-PAC-1 mAb, or FITC-fibrinogen in the presence of PT25-2 mAb, indicating that this variant impacts protein function (PMID: 12506038; PS3). Finally, This variant is absent from gnomAD v2.1.1 (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: PP4, PP3 and PM2_Supporting, PS3 (VCEP specifications version 2).