ClinVar Miner

Submissions for variant NM_000212.3(ITGB3):c.62C>T (p.Ala21Val)

gnomAD frequency: 0.00010  dbSNP: rs772418775
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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 RCV003464114 SCV004190245 uncertain significance Glanzmann thrombasthenia 2023-12-19 reviewed by expert panel curation The c.62>T variant in ITGB3 is a missense variant predicted to cause substitution of alanine by valine at amino acid 21. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002964 (310122 alleles) in the Latino/Admixed American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.034, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGB3 function (BP4). The computational splicing predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BP4.
GeneDx RCV000523191 SCV000619367 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing The A21V variant in the ITGB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A21V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A21V as a variant of uncertain significance.

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