Submissions for variant NM_000419.5(ITGA2B):c.526C>G (p.Pro176Ala)

gnomAD frequency: 0.00001  dbSNP: rs2048640485

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225231	SCV001397481	pathogenic	Glanzmann thrombasthenia	2020-09-08	reviewed by expert panel	curation	The c.526C>G (p.Pro176Ala) variant has been reported, in the homozygous state, in at least one proband (PMID: 10607701) with a phenotype highly specific to GT. The variant cosegregated with disease in this proband and a sibling. Additionally two compound heterozygous cases have been reported (PMIDs: 10607701, 12083483). It is absent from Exac and gnomAD and multiple lines of computational evidence support a deleterious effect (REVEL score of 0.825). Expression of Pro176Ala in COS-1 and CHO cells demonstrated decreased surface expression and indicated the ability of αIIbβ3 to interact with immobilized fibrinogen was attenuated and abolished for soluble fibrinogen (PMID: 10607701). In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS3, PM2_Supporting, PM3_Supporting, PP1, PP3, and PP4_Strong.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001796397	SCV002034026	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001796397	SCV002037435	pathogenic	not provided		no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002245882	SCV002515507	likely pathogenic	Glanzmann thrombasthenia 1		no assertion criteria provided	clinical testing