Submissions for variant NM_000419.5(ITGA2B):c.2473_2478delinsTCACCAGGGCCTTCACCTCAGCATCCACCAG (p.Val825fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003459894	SCV004190250	pathogenic	Glanzmann thrombasthenia	2023-10-17	reviewed by expert panel	curation	The c.2473_2478delinsTCACCAGGGCCTTCACCTCAGCATCCACCAG frameshift variant in ITGA2B occurs within exon 25. It is predicted to result in an out of frame deletion of 6 bp and an insertion of 31 bp at the beginning of exon 25 of the GPllb gene. This is predicted to result in a frameshift with a premature stop codon in exon 27 of 30, which would be expected to result in NMD. However, the predominant platelet GPIIb mRNA of the proband, reported in PMID: 7529063, was a product of the splicing of exon 24 to a cryptic AG acceptor site in the insertion and encodes for a substitution of 10 amino acids Leu817-Asn826 by an altered sequence of 8 amino acids, followed by normal translation of the rest of the protein. Overall the protein had a length reduction of 2 amino acids (PM4). At least one patient (Patient 1 in PMID: 7529063) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, immunoblotting showed small amounts of GPIIIa and minute amounts of pro-GPIlb confirming type 1 GT (PP4_moderate). The variant has been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus one affected family member (PMID: 7529063) , both with the homozygous genotype with the p.Val825SerfsTer? variant (PP1; PM3_supporting). Surface expression of αIIbβ3 measured by flow cytometry in COS-7 cells transiently co-transfected with the c.2473_2478delinsTCACCAGGGCCTTCACCTCAGCATCCACCAG variant αIIb and wild type β3 showed decreased expression at <5% WT levels, indicating that this variant impacts protein function (PMID:7529063 )(PS3). 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: PS3, PP4_Moderate, PM4, PP1, PM2_Supporting and PM3_Supporting (VCEP specifications version 2).