ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.310+1G>A

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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 RCV003222556 SCV003915970 pathogenic Glanzmann thrombasthenia 2023-01-17 reviewed by expert panel curation The NM_000419.5(ITGA2B):c.310+1G>A variant disrupts the donor splice site in intron 2, which is predicted to cause the skipping of exon 2, leading to a frameshift with a premature stop codon in exon 3 which may trigger nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). At least one patient (Patient 3 in PMID:19172520/GT database record 160) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was reduced to <10%, as measured by flow cytometry. Patient 3 (PMID: 19172520/GT database record 160) is homozygous for this variant (0.5pt; PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001771 (2/112928 alleles) in the European non-Finnish population, which is lower than the ClinGen PD VCEP threshold (<0.0001; 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 2.1).

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