SOS1 p.Phe623Ile

The c.1867T>A (p.Phe623Ile) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of Noonan syndrome (PS2; PMID 17586837, 20673819). The p.Phe623Ile variant has also been identified in another independent occurrence in a patient with clinical features of Noonan syndrome (PS4_Supporting; PMID 20673819). This variant was absent from large population studies (PM2; gnomAD; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Phe623Ile variant may impact the protein (PP3). The variant is located in the SOS1 gene, which 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). Of note, two different pathogenic missense variants have been previously reported at this codon of SOS1 (p.Phe623Val and p.Phe623Glu) which may indicate that this residue is critical to the function of the protein, however these variants have not yet met the criteria to be classified as pathogenic (PM5 not met). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM2, PP2, PP3.