Submissions for variant NM_000419.5(ITGA2B):c.1021G>A (p.Ala341Thr)

dbSNP: rs2048616842

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001290494	SCV001478533	likely pathogenic	Glanzmann thrombasthenia	2024-03-07	reviewed by expert panel	curation	The NM_000419.5:c.1021G>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 341. At least one patient (Patient 5 in PMID:32089034) homozygous for this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). A second homozygous case has also been identified (Northern Blood Research Centre, Kolling Institute, at The University of Sydney; PM3). This variant occurs at a MAF of 0.000002737 (3/1096028 alleles) in the European (non-Finnish) population, which is below the <0.0001 threshold for PM2_supporting. The computational predictor REVEL gives a score of 0.737, 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_moderate, PM3, PM2_supporting, PP3. (VCEP specifications version 2).
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313793	SCV004013052	likely pathogenic	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing