Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002511532 | SCV002820924 | pathogenic | Glanzmann thrombasthenia | 2022-08-05 | reviewed by expert panel | curation | The NM_000419.5:c.1599_1600del (p.Ser534ProfsTer) variant in ITGA2B exon 16 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 17/30 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Although in silico tools predict the gain of a splice donor site 3 bp downstream that could lead to reading frame restoration, RT-PCR analysis of this region using RNA from a patient homozygous for the variant (GT-10, PMID: 25539746) confirmed the presence of mRNA with the 2 bp deletion and did not identify evidence of a restored reading frame (personal communication with Dr. Jose_x0019_ Rivera (Servicio de Hematolog_x0019_ıa y Oncolog_x0019_ıa Me_x0019_dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacio_x0019_n, Universidad de Murcia)). This variant has been detected in homozygosity in at least one proband with Glanzmann thrombasthenia (GT-10, PMID: 25539746). Total points: 0.5 (PM3_Supporting). This patient (Patient GT-10 in PMID: 25539746) displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). 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: PVS1, PP4_Moderate, PM2_Supporting, PM3_Supporting. (VCEP specifications version 2; date of approval 08/04/2022) |