ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.555T>G (p.Ile185Met)

dbSNP: rs2048639927
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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 RCV001225226 SCV001397472 likely pathogenic Glanzmann thrombasthenia 2023-10-17 reviewed by expert panel curation The ITGA2B missense variant NM_000419.4:c.555T>G replaces the isoleucine residue with a methionine residue (p.Ile185Met). This variant has been observed in a proband with a phenotype specific for Glanzmann's thrombasthenia (GT; PP4_Strong) who also harbors a second ITGA2B variant (c.1882C>T, p.Arg628Ter) previously classified by the VCEP as pathogenic (phase unconfirmed; PM3_supporting). Furthermore, this variant has not been observed in population databases (absent from gnomAD v2.1.1 and v3; PM2_supporting). Although the in silico meta-predictor REVEL score for this variant is 0.134 (below the VCEP-established threshold of 0.25) and multiple other in silico tools also predict no impact on the gene product, splicing tools predict this variant creates an exonic cryptic donor site (SpliceAI delta score 0.89), potentially altering splicing. Given the conflicting in silico predictions for this variant, neither BP4 nor PP3 was applied. Experimental evidence is needed to clarify the effect of the variant on the gene product. In summary, this variant is classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PP4_strong, PM3_supporting.

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