Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000121910 | SCV000712324 | uncertain significance | not specified | 2016-06-24 | criteria provided, single submitter | clinical testing | The p.Glu532Lys variant in PTPN11 has not been previously reported in individual s with clinical features of a RASopathy, but has been identified in 1/11574 Lati no chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs587778634). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, the clinical significan ce of the p.Glu532Lys variant is uncertain. |
| Genome Diagnostics Laboratory, |
RCV001813380 | SCV002060836 | uncertain significance | Noonan syndrome and Noonan-related syndrome | 2021-05-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001854671 | SCV002176997 | uncertain significance | RASopathy | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 532 of the PTPN11 protein (p.Glu532Lys). This variant is present in population databases (rs587778634, gnomAD 0.009%). 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: 135111). 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. |
| Fulgent Genetics, |
RCV002483228 | SCV002781341 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2022-05-26 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003298143 | SCV004000112 | uncertain significance | Cardiovascular phenotype | 2023-06-13 | criteria provided, single submitter | clinical testing | The p.E532K variant (also known as c.1594G>A), located in coding exon 13 of the PTPN11 gene, results from a G to A substitution at nucleotide position 1594. The glutamic acid at codon 532 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in a Noonan-like syndrome cohort (Brasil AS et al. Genet Test Mol Biomarkers, 2010 Jun;14:425-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| ITMI | RCV000121910 | SCV000086114 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |