ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.1639T>G (p.Cys547Gly)

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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 RCV002511546 SCV002820942 likely pathogenic Glanzmann thrombasthenia 2022-03-07 reviewed by expert panel curation The NM_000212.3:c.1639T>G variant in ITGB3 is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 547 (p.Cys547Gly). This variant has been observed in compound heterozygosity in one individual (Patient 3 in PMID: 28748566) in combination with ITGB3 variant c.1192delG (p.Ala398ProfsTer24, provisionally classified as pathogenic by the Platelet Disorders VCEP, trans phase not confirmed) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). This variant is very rare in the general population, occurring at a frequency of 0.0065% in the non-Finnish European subpopulation of gnomAD v2.1.1 (PM2_Supporting). Surface expression of β3 and αIIbβ3 measured by Western blot and flow cytometry (respectively) in HEK293 cells transiently co-transfected with p.Cys547Gly variant β3 and wild type αIIb showed decreased expression at <5%, indicating that this variant impacts protein function (PMID: 25827233) (PS3). Furthermore, the computational predictor REVEL gives a score of 0.993, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets the 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: PS3, PM2_Supporting, PM3_Supporting, PP3, PP4_Moderate. (VCEP specifications version 2; date of approval 2/3/2022)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003493963 SCV004242864 likely pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing

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