ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.188_189delinsGC (p.Tyr63Cys) (rs1057517917)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413931 SCV000491066 pathogenic not provided 2015-09-16 criteria provided, single submitter clinical testing To our knowledge, the c.188_189delATinsGC pathogenic variant in the PTPN11 gene has not been previously reported in association with a disorder in the Noonan syndrome spectrum. The c.188_189delATinsGC deletion/insertion causes a missense change at codon Tyrosine 63, changing this amino acid to a Cysteine residue, Y63C, which has been reported previously in association with autosomal dominant Noonan syndrome (Tartaglia et al., 2001). The Y63C pathogenic variant lies in the N-SH2 domain of the SHP2 protein encoded by PTPN11. This domain is the first of two sites involved in switching the protein between its inactive and active conformations. Functional studies demonstrated that Y63C perturbs the stability of the SHP2 protein in its inactive conformation and promotes a significant up-regulation in protein function (Martinelli et al., 2012). The c.188_189delATinsGC varaint 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 non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, missense variants in nearby residues (N58D/H/K, T59A, G60S/C/A, D61N/H/A, Y62N/D/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. Therefore, the c.188_189delATinsGC variant is consistent with a diagnosis of a disorder in the Noonan syndrome spectrum.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.