PTPN11 NM_001330437.1:c.127C>T, Leu43Phe

ClinVar contains an entry for this variant (Variation ID: 561500). This missense change has been observed in individual(s) with complete atrioventricular septal defect and/or Noonan syndrome (PMID: 15940693; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 43 of the PTPN11 protein (p.Leu43Phe). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: PTPN11 c.127C>T (p.Leu43Phe) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.127C>T has been reported in the literature in an individual affected with atrioventricular septal defect (Weismann_2005). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. The variant is located close to a known Noonan syndrome mutation (PTPN11 p.T42A) and it is part of a group of variants located in the phosphopeptide-binding clefts in the N-terminal SH2 domain which are implicated in the intermolecular interactions of the protein with its signaling partners and which control SHP-2 translocation and activation. Mutations affecting these pockets are predicted to perturb phosphopeptide-binding specificity and/or affinity (Lappalainen_2008, Tartaglia_2006). However, to our knowledge, no experimental evidence demonstrating an impact of the variant on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and as likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional data of clinical and functional significance become available.