ClinVar

Description

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.