Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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, |
RCV002495890 | SCV002801480 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2022-03-08 | criteria provided, single submitter | clinical testing | |
| Invitae | 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. |