Submissions for variant NM_002834.5(PTPN11):c.865A>G (p.Arg289Gly)

dbSNP: rs2135901005

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001557643	SCV001779438	uncertain significance	not provided	2019-04-25	criteria provided, single submitter	clinical testing	Reported in two unrelated patients with Noonan syndrome in published literature, but no phenotype information was provided (Yu et al., 2019); Functional studies show R289G may lead to a slight decrease in catalytic activity (Bentires-Alj et al., 2004); the mechanism of disease for PTPN11 variants is usually gain-of-function; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 16631468, 15604238, 18470943, 30896080)
Fulgent Genetics, Fulgent Genetics	RCV002495890	SCV002801480	uncertain significance	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-03-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003120628	SCV003786591	likely pathogenic	RASopathy	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 289 of the PTPN11 protein (p.Arg289Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 30896080). ClinVar contains an entry for this variant (Variation ID: 1194782). 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) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 18470943). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV004656627	SCV005155786	uncertain significance	Cardiovascular phenotype	2024-04-24	criteria provided, single submitter	clinical testing	The p.R289G variant (also known as c.865A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at nucleotide position 865. The arginine at codon 289 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in a Noonan syndrome cohort; however, clinical details were limited (Yu KPT et al. Am J Med Genet C Semin Med Genet, 2019 Jun;181:208-217). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.