Submissions for variant NM_002834.5(PTPN11):c.893A>G (p.Asn298Ser)

gnomAD frequency: 0.00004  dbSNP: rs572274623

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159053	SCV000208995	uncertain significance	not provided	2017-08-22	criteria provided, single submitter	clinical testing	The N298S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant was identified in one individual referred for Noonan syndrome genetic testing who was positive for another pathogenic variant in PTPN11 at GeneDx. This variant is not observed at significant frequencies in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N298S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position where amino acids with similar properties to asparagine (N) are tolerated across species, and serine (S) is tolerated at this position in at least one species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Blueprint Genetics	RCV000208167	SCV000264158	uncertain significance	Cardio-facio-cutaneous syndrome	2015-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844054	SCV002103678	uncertain significance	not specified	2022-02-28	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.893A>G (p.Asn298Ser) results in a conservative amino acid change located in the Tyrosine-specific protein phosphatase, PTPase domain (IPR000242) of the encoded protein sequence. Four 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 251432 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PTPN11 causing Noonan Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.893A>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001850234	SCV002128665	uncertain significance	RASopathy	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 298 of the PTPN11 protein (p.Asn298Ser). This variant is present in population databases (rs572274623, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 181500). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002372037	SCV002687425	likely benign	Cardiovascular phenotype	2020-08-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002492630	SCV002775538	uncertain significance	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-09-09	criteria provided, single submitter	clinical testing