ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1402_1403delinsGA (p.Thr468Glu) (rs886039711)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254759 SCV000322658 pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing The c.1402_1403delACinsGA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant results in a missense change, replacing Threonine 468 with a Glutamic acid (T468E). The c.1402_1403delACinsGA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the tyrosine-phosphatase domain that is conserved across species; additionally, T468 is known to be a critical residue in the active site of this domain (Digilio et al., 2002; Martinelli et al., 2008). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (T468P/M) and in a nearby residue (G464A) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.

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