ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.1260G>A (p.Thr420=)

gnomAD frequency: 0.00001  dbSNP: rs74458693
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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 RCV001290478 SCV001478516 likely pathogenic Glanzmann thrombasthenia 2023-11-02 reviewed by expert panel curation The ITGB3 synonymous variant NM_000212.3:c.1260G>A is predicted to lead to loss of the adjacent canonical splice donor and in vitro minigene assays and sequence analysis of patient mRNA suggest the variant results in the in frame deletion of exon 9 (PMID: 8878424; PM4). This variant has been observed in homozygosity in two individuals (Patient RS in PMID: 8878424 and GT50 in PMID: 25728920; PM3), at least one of which was reported to have a phenotype specific for Glanzmann's thrombasthenia (PMID: 25728920, GT50; PP4_moderate). Furthermore, the variant is rare in control population databases (MAF<1/10,000; PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM3, PM4, PM2_supporting, PP3, PP4_moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV003546696 SCV004267772 pathogenic not provided 2023-10-29 criteria provided, single submitter clinical testing This sequence change affects codon 420 of the ITGB3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ITGB3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs74458693, gnomAD 0.004%). This variant has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 8878424, 25728920, 30138987). This variant is also known as position 20624G>A. ClinVar contains an entry for this variant (Variation ID: 996184). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9 and activation of a cryptic splice site and introduces a premature termination codon (PMID: 8878424). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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