Submissions for variant NM_000419.5(ITGA2B):c.212C>G (p.Pro71Arg)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003234996	SCV003934979	likely pathogenic	Glanzmann thrombasthenia	2023-06-01	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.212C>G (p.Pro71Arg) missense variant has been reported in at least one Glanzmann thrombasthenia patient (PMID: 21113249). Patient GE 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 <1%, as measured by flow cytometry, and there was<1% binding to PAC-1. (PP4_strong). The full genotype of Patient GE was reported later in Pilgrimm-Thorp (2012) Haemophilia 18S3 157 and a PhD dissertation from D. Pillitteri, the patient is compound heterozygous for this variant and Leu684Arg (classified VUS by the PD VCEP; PM3_NotMet). The Pro71Arg variant is absent from gnomAD v2.1.1 (PM2_Supporting) and the computational predictor REVEL gives a score of 0.809, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). 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_strong, PM2_supporitng, PP3_supporting.