ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.836A>T (p.Lys279Met)

gnomAD frequency: 0.00001  dbSNP: rs79775494
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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 RCV001580229 SCV001809864 uncertain significance Glanzmann thrombasthenia 2021-08-17 reviewed by expert panel curation The ITGB3 missense variant NM_000212.3:c.836A>T replaces the lysine residue with a methionine residue (p.Lys279Met) and is absent from control population databases. The variant is predicted by in silico tools to be damaging to protein function. The functional impact has been assessed by flow cytometric detection of αIIb, β3, and αIIbβ3 positive cells following transient transfection of ITGB3 cDNA carrying this variant, showing a reduction in the number cells positive for the αIIbβ3 complex (estimated to be ~7% compared to wild type; PMID: 20020534). This variant has been observed in heterozygosity in an individual suspected to have Glanzmann's thrombasthenia (GT) (CabGT-24 in PMID: 20020534), however sufficient information to confirm if the individual's phenotype is specific for GT was not provided and the second ITGB3 variant identified in the individual is of uncertain significance and unknown phase. In summary, this variant is of uncertain significance and lacks sufficient evidence to be classified as pathogenic or benign for GT. GT-specific criteria applied: PS3_supporting, PM2_supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV003556016 SCV004298258 uncertain significance not provided 2023-06-24 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ITGB3 protein function. ClinVar contains an entry for this variant (Variation ID: 13568). This missense change has been observed in individual(s) with Glanzmann thrombasthenia (PMID: 20020534). This variant is present in population databases (rs79775494, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 279 of the ITGB3 protein (p.Lys279Met).
OMIM RCV000014536 SCV000034787 pathogenic Glanzmann thrombasthenia 2 2010-03-01 no assertion criteria provided literature only

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