PTPN11 NM_001330437.1:c.782T>A, Leu261His

The c.782T>A (p.Leu261His) variant in PTPN11 is present in 1/6064 “other” alleles in gnomAD v2.1.1; however, it is absent from gnomAD v3 (PM2 not met). It has been identified in 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 28074573, 22253195, 23756559). A functional assay performed on this variant does not meet approved RASopathy VCEP guidelines for criteria application (PS3 not met; PMID: 28074573). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of PTPN11 (PM1; PMID 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM1, PP2.

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 261 of the PTPN11 protein (p.Leu261His). This variant is present in population databases (rs765642157, gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome(NS) (PMID: 22253195, 23756559, 28074573). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 575203). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 28074573). This variant disrupts the p.Leu261 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28074573). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.