Submissions for variant NM_000419.5(ITGA2B):c.470C>A (p.Pro157His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003222563	SCV003915980	pathogenic	Glanzmann thrombasthenia	2023-02-02	reviewed by expert panel	curation	The NM_000419.5:c.470C>A variant in ITGA2B is a missense variant predicted to cause substitution of Proline by Histidine at amino acid 157 (p.Pro157His). At least one patient (Patient 1 in PMID: 18976939) with this variant 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 0%, as measured by flow cytometry and Western blot. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). Surface expression of αIIbβ3 measured by flow cytometry in CHO cells transiently co-transfected with the NM_000419.5:c.470C>A (p.Pro157His) variant αIIb and wild type αIIb showed decreased expression at 0% of WT levels, indicating that this variant impacts protein function (PMID: 18976939)(PS3). The computational predictor REVEL gives a score of 0.782, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant has been detected in at least 1 probands with Glanzmann thrombasthenia. This individual was homozygous for the variant (PMID: 18976939, 0.5 PM3 points) Total points: 0.5 (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Strong, PS3, PP3, PM2_Supporting and PM3_Supporting (VCEP specifications version 2).