ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.225_226del (p.Ala76fs)

dbSNP: rs1438135616
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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 RCV001803406 SCV002047556 pathogenic Glanzmann thrombasthenia 2021-11-09 reviewed by expert panel curation NM_000212.3(ITGB3):c.225_226del (p.Ala76ProfsTer10) in exon 3 of ITGB3 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3/15 and is predicted to lead to nonsense mediated decay (PVS1). GT7 of PMID: 32237906 displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, β3 surface expression was reduced to 0.3%, as measured by flow cytometry. GT7 (PMID: 32237906) is compound heterozygous for c.225_226del and Arg242Ter (classified Pathogenic by the PD-VCEP; PM3_supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001087 (2/18394 alleles) in the East Asian 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 Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PP4_moderate, PM2_supporting, PM3_supporting. (VCEP specifications version 2; date of approval 11/04/2021)
Labcorp Genetics (formerly Invitae), Labcorp RCV003728011 SCV004522616 pathogenic not provided 2023-05-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala76Profs*10) in the ITGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ITGB3 are known to be pathogenic (PMID: 21917754). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ITGB3-related conditions. For these reasons, this variant has been classified as Pathogenic.

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