PTPN11 NM_001330437.1:c.1052G>A, Arg351Gln

Variant summary: PTPN11 c.1052G>A (p.Arg351Gln) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of 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 0.00043 in 251446 control chromosomes. The observed variant frequency is approximately 6.81 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome phenotype (6.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1052G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories and an expert panel (ClinGen RASopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.