The c.1678C>T (p.Leu560Phe) variant in PTPN11 (NM_002834.5(PTPN11):c.1678C>T (p.Leu560Phe)) has been identified in individuals with some features of a RASopathy but none were diagnosed with a RASopathy (PS4 not met; GeneDx, Partners LMM, APHP-Robert Debré Hospital internal data; GTR ID's: 28338, 26957, 21766; SCV000061285.5; SCV000208999.2; SCV000207690.1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data: GTR ID: 26957; SCV000208999.2). In vitro functional studies provide some evidence that the p.Leu560Phe variant does not impact protein function (BS3; PMID: 15987685). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied: BS3, BP5 (Version 2.1; 09/17/2024).

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: PTPN11 c.1678C>T (p.Leu560Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251088 control chromosomes (gnomAD). This frequency is not higher than predicted for a pathogenic variant in PTPN11 causing Noonan Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.1678C>T has been reported in the literature in at-least one individual affected with Hypertrophic Cardiomyopathy (example, Sarkozy_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on biochemical function (example, Keilhack_2005). Eight clinical diagnostic laboratories including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) and uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 560 of the PTPN11 protein (p.Leu560Phe). This variant is present in population databases (rs397516797, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome and congenital hypertrophic cardiomyopathy (PMID: 12960218). ClinVar contains an entry for this variant (Variation ID: 44599). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change does not substantially affect PTPN11 function (PMID: 15987685). 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.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).