ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.1423C>T (p.Gln475Ter)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV004577685 SCV005061693 pathogenic Glanzmann thrombasthenia 2024-02-20 reviewed by expert panel curation The c.1423C>T (p.Gln475Ter) variant is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established mechanism (PVS1; PMID:31980526). At least one patient (Patient 8 in PMID:36672149) 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 absent (<25%), as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_moderate). The same individual was homozygous for the variant and confirmed in trans (0.5 PM3 points, PMID:36672149). Total points: 0.5 (PM3_supporting). This variant is absent from gnomAD v.2.1.1 (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: PVS1, PM3_supporting, PM2_supporting, PP4_moderate. (VCEP specifications version 2; date of approval 02/20/2024)

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