ClinVar

Description

The p.G503R pathogenic mutation (also known as c.1507G>C), located in coding exon 13 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1507. The glycine at codon 503 is replaced by arginine, an amino acid with dissimilar properties, and is located in the PTP domain of the PTPN11 protein. This mutation has been reported in multiple individuals with Noonan syndrome, including at least two affected parent-child pairs (Sarkozy A et al. J Med Genet, 2003 Sep;40:704-8; Lo FS et al. Int J Hematol, 2008 Oct;88:287-290; Bessis D et al. Br J Dermatol, 2019 06;180:1438-1448). The same amino acid substitution caused by a different nucleotide change (c.1507G>A) has also been reported in individuals with Noonan syndrome (Tartaglia M et al. Am J Hum Genet, 2006 Feb;78:279-90; Athota JP et al. BMC Med Genet, 2020 03;21:50). There have been reports of a few individuals with p.G503R and Noonan syndrome diagnosed with juvenile myelomonocytic leukemia (JMML) (Strullu M et al. J Med Genet, 2014 Oct;51:689-97; Kratz CP et al. Br J Cancer, 2015 Apr;112:1392-7). In addition, other alterations at the same residue (p.G503A and p.G503E) have also been described in individuals with features of Noonan syndrome (Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Jongmans MC et al. Eur. J. Hum. Genet., 2011 Aug;19:870-4). Based on internal structural analysis, p.G503R is more destabilizing than other nearby pathogenic variants (Hof P et al. Cell, 1998 Feb;92:441-50). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.