Submissions for variant NM_000419.5(ITGA2B):c.2944G>A (p.Val982Met)

gnomAD frequency: 0.00001  dbSNP: rs78657866

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225295	SCV001397574	pathogenic	Glanzmann thrombasthenia	2020-09-06	reviewed by expert panel	curation	The c.2944G>A (p.Val982Met) missense variant has been reported in at least three compound heterozygous probands with a phenotype highly specific to GT (PMID: 28983057, 25539746,15099289); one of which was a de novo occurrence (PMID: 25539746). It is found at an extremely low frequency (MAF of 0.00006486 in the non-Finnish European population from gnomAD). This variant is predicted by HSF and MaxEntScan to result in a broken splice donor site. Flow cytometry found that this variant had a marked deleterious effect on αIIbβ3 expression (~25% of control levels) in COS-7 cells (PMID: 15099289). In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PS2, PM3, PM2_supporting, PS3_Moderate, PP3, and PP4_moderate.
GeneDx	RCV000443560	SCV000521349	likely pathogenic	not provided	2016-09-27	criteria provided, single submitter	clinical testing	The V982M variant in the ITGA2B gene has been reported previously (as V951M due to the use of alternate nomenclature) in assocation with Glanzmann thrombasthenia (Nurden et al., 2004; Jallu et al., 2010). In one individual, V982M was identified in the compound heterozygous state with a splice site variant (Nurden et al., 2004), while in another individual, no second pathogenic variant was identified (Jallu et al., 2010). The V982M variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V982M variant is a conservative amino acid substitution, which occurs at a position that is conserved in mammals. Functional studies demonstrate that V982M results in significant loss of ITGA2b protein surface expression (Nurden et al., 2004). The V982M variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002225613	SCV002505357	pathogenic	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing