ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.778-2A>G

gnomAD frequency: 0.00001  dbSNP: rs749261962
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV000761245 SCV005061683 uncertain significance Glanzmann thrombasthenia 2024-05-02 reviewed by expert panel curation The variant NM_000212.3(ITGB3):c.778-2A>G occurs within a canonical splice site and is predicted to cause skipping of biologically-relevant-exon 6, resulting in an in-frame deletion, removing amino acids Glu260 to Met313, and removing <10% of the protein (PVS1_Moderate). The variant has a rate of 0.00004846 (2/41268 alleles) in the East Asian population in gnomADv4.0.0, which is less than the threshold (<0.0001) for PM2_Supporting. The variant has been found in at least one individual with GT, ClinVar entry (SCV000891201.1) by the Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota. The patient is compound heterozygous with Likely Pathogenic variant NM_000212.3(ITGB3):c.325del (p.Val109SerfsTer?), phasing not confirmed. The patient had bleeding since childhood, abnormal aggregation, and flow cytometry low levels of GPIIb/IIIa. Patient information is consistent with GT but insufficient for PP4. In summary, this variant meets the criteria to be classified as variant of uncertain significance- insufficient evidence for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_moderate, PM2_supporting (PD VCEP specifications version 2.1).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761245 SCV000891201 likely pathogenic Glanzmann thrombasthenia 2017-12-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003558560 SCV004305155 likely pathogenic not provided 2023-08-28 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with ITGB3-related conditions. This variant is present in population databases (rs749261962, gnomAD 0.01%). This sequence change affects an acceptor splice site in intron 5 of the ITGB3 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 ITGB3 are known to be pathogenic (PMID: 21917754). ClinVar contains an entry for this variant (Variation ID: 623143). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.

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