Submissions for variant NM_000419.5(ITGA2B):c.2264G>A (p.Arg755Gln)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003222566	SCV003915985	uncertain significance	Glanzmann thrombasthenia	2023-03-21	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.2264G>A (p.Arg755Gln) missense variant has been reported in two related individuals previously (GT35a,b in PMID: 25728920) who additionally had two variants Arg131pro and c.777+1G>A on the ITGB3 gene which have been evaluated to be likely pathogenic and pathogenic respectively by ClinGen Platelet VCEP so the impact of the ITGA2B variant is unclear. The gnomADv2.1.1 allele frequency for the Latino subpopulation is 0.0001903 (6/31522 alleles) which is not <0.01%, therefore PM2_supporting is not met and REVEL score is 0.68, which is below the recommended threshold of >0.70. Another missense change at this residue, Arg755Pro, has been reported previously and assessed to be Likely Pathogenic by ClinGen Platelet Disorder VCEP (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for GT. GT-specific criteria applied: PM5_supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317669	SCV004020607	uncertain significance	not specified	2023-06-07	criteria provided, single submitter	clinical testing	Variant summary: ITGA2B c.2264G>A (p.Arg755Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Another missense variant affecting this residue (p.Arg755Pro) has been classified as likely pathogenic by a ClinGen expert panel. The variant allele was found at a frequency of 5.6e-05 in 212602 control chromosomes (gnomAD). c.2264G>A has been reported in the literature in two siblings affected with Glanzmann thrombasthenia 1 (Nurden_2015). This report does not provide unequivocal conclusions about association of the variant with Glanzmann thrombasthenia 1. Co-occurrences with other pathogenic/likely pathogenic variants were reported in the aforementioned individuals (ITGB3 c.392G>C, p.Arg131Pro; ITGB3 c.777+1G>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25728920). One submitter, a ClinGen expert panel, has provided a clinical-significance assessment for this variant to ClinVar after 2014, and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.