Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000681136 | SCV000808594 | uncertain significance | not provided | 2018-03-07 | criteria provided, single submitter | clinical testing | The Y263C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y263C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y263C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Pathogenic and likely pathogenic missense variants in nearby residues (G258D, L261F, L262R, R265Q, G268S, G268C) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Ambry Genetics | RCV002406523 | SCV002675591 | uncertain significance | Cardiovascular phenotype | 2020-02-18 | criteria provided, single submitter | clinical testing | The p.Y263C variant (also known as c.788A>G), located in coding exon 7 of the PTPN11 gene, results from an A to G substitution at nucleotide position 788. The tyrosine at codon 263 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV002493128 | SCV002776463 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2021-11-20 | criteria provided, single submitter | clinical testing | |
Invitae | RCV003768042 | SCV004678912 | uncertain significance | RASopathy | 2023-07-29 | criteria provided, single submitter | clinical testing | 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. 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. 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: 561753). This variant is present in population databases (rs763617831, gnomAD 0.003%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 263 of the PTPN11 protein (p.Tyr263Cys). |