ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.180_181delinsAA (p.Asp61Asn) (rs1057517935)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412983 SCV000491105 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing To our knowldege, the c.180_181delTGinsAA variant in the PTPN11 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant. The c.180_181delTGinsAA variant results in an in-frame deletion leading to the the replacement of an Aspartic acid residue by an Asparagine residue, denoted p.Asp61Asn (D61N). Another nucleotide change (c.181 G>A), also leading to the D61N missense change has been published previously in association with Noonan syndrome (Stenson et al., 2014). The c.180_181delTGinsAA 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. It 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 hotspot N-SH2 domain where the Aspartic acid residue is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants at the same codon (D61H/G/A) and in nearby residues (Y62D/N/C, G60A/S/C) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein.

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