Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000265572 | SCV000330273 | uncertain significance | not provided | 2016-02-28 | criteria provided, single submitter | clinical testing | The G39R variant in the PTPN11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G39R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G39R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (T42A and L43F) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Although this individual's presumably unaffected mother also harbors the G39R variant, greatly variable expressivity with frequent subtlety of features has been reported for Noonan spectrum disorders (Allanson et al., 2011). We interpret G39R as a variant of uncertain significance |
| Invitae | RCV002519051 | SCV003217489 | uncertain significance | RASopathy | 2022-06-27 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 280367). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 39 of the PTPN11 protein (p.Gly39Arg). |
| Clinical Genetics Laboratory, |
RCV001528118 | SCV001739325 | likely pathogenic | LEOPARD syndrome 1 | 2021-02-15 | no assertion criteria provided | clinical testing |