Submissions for variant NM_000419.5(ITGA2B):c.89G>A (p.Trp30Ter)

dbSNP: rs1131692013

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002254699	SCV002525920	uncertain significance	Glanzmann thrombasthenia	2022-09-20	reviewed by expert panel	curation	The NM_000419.5:c.89G>A (p.Trp30Ter) variant in exon 1 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 1/30. NMD is not predicted based on PMID: 21389146 reporting that NMD is not triggered by termination codons within exon 1/ first 100 nucleotides. Therefore, PVS1 is downgraded to PVS1_Moderate. The Trp30Ter nonsense variant has not been reported in patients with GT in the literature, to the best of our knowledge. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002891(1/34592 alleles) in the Latino/Admixed American population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). In summary, the significance of this variant for autosomal recessive Glanzmann Thrombasthenia is uncertain based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Moderate, PM2_Supproting. (VCEP specifications version 2; date of approval: April 7, 2022)
GeneDx	RCV000493309	SCV000583366	likely pathogenic	not provided	2017-05-31	criteria provided, single submitter	clinical testing	The W30X variant in the ITGA2B gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W30X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret W30X as a likely pathogenic variant.