ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.188G>A (p.Arg63Lys)

dbSNP: rs767688038
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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 RCV002254825 SCV002525921 likely pathogenic Glanzmann thrombasthenia 2022-06-13 reviewed by expert panel curation The NM_000419.5:c.188G>A variant in ITGA2B is a missense variant predicted to cause substitution of Arginine by Lysine at amino acid 63 (Arg63Lys). At least one patient (1yo female proband from Morocco in PMID:12871379) with this variant 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 <10% (threshold: <25%), as measured by flow cytometry and Western blot. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong, PMID: 12871379). This variant has been detected in homozygosity in at least 1 proband with Glanzmann thrombasthenia. Parents were heterozygous. (0.5pts, PMID: 12871379). Total points: 0.5 (PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008803 (1/113594 alleles) in the non-Finnish European population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). 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: PP4_Strong, PM2_Supporting, PM3_Supporting. (VCEP specifications version 2; date of approval April 7, 2022)

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