ClinVar Miner

Submissions for variant NM_000212.2(ITGB3):c.187C>T (p.Arg63Cys) (rs199866795)

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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 RCV000778500 SCV001397580 likely pathogenic Glanzmann thrombasthenia 2020-06-15 reviewed by expert panel curation The missense variant, c.187C>T (p.Arg63Cys), has been reported in one compound heterozygous proband (PMID: 25728920). It occurs at an extremely low frequency, with an overall allele frequency in gnomAD of 0.00002476 (MAF of 0.00005012 in the East Asian population). SIFT, PolyPhen, and MutationTaster agree that the Arg63Cys variant is damaging/disease causing (REVEL score of 0.98). In transiently transfected COS-7 cells expressing Arg63Cys mutant integrin FACS analysis showed 85% reduction of alphaIIbbeta3Cys63 expression. In summary, this variant meets criteria to be classified as Likely Pathogenic for GT. GT-specific criteria applied: PS3_Moderate, PM2_Supporting, PM3_Supporting, PP3, and PP4_Moderate.
Illumina Clinical Services Laboratory,Illumina RCV000778500 SCV000914771 uncertain significance Glanzmann thrombasthenia 2017-04-27 criteria provided, single submitter clinical testing The ITGB3 c.187C>T (p.Arg63Cys) variant has been reported in one study and was found in a compound heterozygous state with a nonsense variant in one patient with Glanzmann thrombasthenia, type II (Nurden et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. When the p.Arg63Cys-containing integrin was transiently expressed in COS-7 cells, αIIbβ3 protein expression was reduced by 85% compared to wild type. Immunoblotting of lysed cells from the patient also showed that pro-αIIb and mature αIIb expression was reduced, indicating that αIIbβ3 complex maturation was slowed or impaired. Based on the evidence, the p.Arg63Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for thrombasthenia of Glanzmann and Naegeli. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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