Submissions for variant NM_000419.5(ITGA2B):c.10G>A (p.Ala4Thr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV004577689	SCV005061698	uncertain significance	Glanzmann thrombasthenia	2024-06-06	reviewed by expert panel	curation	The c.10G>A variant in ITGA2B is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 4. At least one patient (Proband 1 in PMID:18788610) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). The highest population minor allele frequency in gnomAD v4.1.0 is 0.001292 58/44900 alleles in the East Asian population, which is below than the ClinGen PD VCEP threshold (>0.00158) for BS1 but above the <0.0001 threshold for PM2_supporting. Furthermore, the computational predictor REVEL gives a score of 0.232, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2B function (BP4). In summary, this variant meets the criteria to be classified as Uncertain significance - conflicting evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_moderate, BP4 (VCEP specifications version 2; date of approval 06/06/2024).