ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.1946+1G>A

gnomAD frequency: 0.00001  dbSNP: rs746091910
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV000689591 SCV001397586 pathogenic Glanzmann thrombasthenia 2020-09-06 reviewed by expert panel curation The splicing variant, c.1946+1G>A, has been observed in at least one compound heterozygous patient in the literature with a phenotype highly specific to GT (PMID: 15099289). The canonical IVS19+1 donor splice site is lost, which is expected to result in skipping of exon 19 causing a reading frame shift with 10 new amino acids followed by a stop codon that leads to NMD. The variant is absent form ExAC, gnomAD, and 1000 Genomes. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV000689591 SCV000817248 likely pathogenic Glanzmann thrombasthenia 2023-08-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the ITGA2B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with autosomal recessive Glanzmann thrombasthenia (PMID: 15099289). This variant is also known as IVS19(+1). ClinVar contains an entry for this variant (Variation ID: 569057). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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