Submissions for variant NM_000419.5(ITGA2B):c.1230del (p.Tyr411fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002511563	SCV002820962	pathogenic	Glanzmann thrombasthenia	2022-12-01	reviewed by expert panel	curation	The c.1230del (p.Tyr411ThrfsTer20) variant in exon 13 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 13 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 9 in PMID: 19172520) 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 < 10% of wild type levels, as measured by flow cytometry (according to GT database). However, ITGA2B and ITGB3 were not [reported to be] sequenced across all exons and intron/exon boundaries (PP4_moderate). This variant has been detected in at least 2 probands with Glanzmann thrombasthenia. One of these probands was homozygous for the variant (0.5 points, PMID: 19172520 ). For the other proband carrying the variant, only one mutated allele was detected in the patient's parents (the father's genotype was wild type and the mother carried the c.1230del frameshift mutation) (0 points, PMID: 31404847). Total points: 0.5 (PM3_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has also not been registered in ClinVar. 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: PVS1, PP4_Moderate, PM2_Supporting and PM3_Supporting (VCEP specifications version 2).