ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.1388G>C (p.Cys463Ser)

dbSNP: rs2143112826
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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 RCV002254822 SCV002525915 likely pathogenic Glanzmann thrombasthenia 2022-04-15 reviewed by expert panel curation The NM_000212.3(ITGB3):c.1388G>C (p.Cys463Ser) missense variant has been observed in at least one GT patient (Patient 7 in PMID: 34267460), whom displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, alphaIIbbeta3 surface expression was reduced to 0.5-1.7%, as measured by flow cytometry (PP4_strong). The variant was been reported to segregate with Glanzmann thrombasthenia in Patient 7 plus one affected family member, both with the homozygous Cys463Ser genotype. (PM3_supporting, PP1; PMID: 34267460). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP1, PP3, PM2_supporting, PM3_supporting. (VCEP specifications version 2.1)

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