PTPN11 and Noonan syndrome: Functional analysis indicates that Noonan syndrome (NS) is caused by gain-of-function PTPN11 variants, whereas LS is caused by autosomal dominant loss-of-function variant.3 The PTPN11 variant (p.Gly464Ala) does not increase PTPN11 activity and is described as a specific causative variant in LS due to the increased bulk of the alanyl side chain caused by Gly464Ala, which blocks the access of the substrate phosphorylation group to the active site.