Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000522529 | SCV000616408 | uncertain significance | RASopathy | 2017-04-03 | reviewed by expert panel | curation | The c.244A>G p.Met82Val variant in PTPN11 has been identified in patients with clinical features of a RASopathy (PS4 not met; GeneDx, EGL genetics internal data; GTR ID's: 26957, 500060; SCV000057386.11; SCV000228999.4). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx internal data; GTR ID's: 26957; SCV000057386.11). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). In summary, the clinical significance of the p.Met82Val variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, PP2. |
| Fulgent Genetics, |
RCV002477045 | SCV002784230 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2024-04-02 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000522529 | SCV001544897 | uncertain significance | RASopathy | 2024-10-18 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 82 of the PTPN11 protein (p.Met82Val). This variant is present in population databases (rs397507515, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 30577886). ClinVar contains an entry for this variant (Variation ID: 40504). Invitae Evidence 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 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. |
| Eurofins Ntd Llc |
RCV000724722 | SCV000228999 | uncertain significance | not provided | 2015-04-16 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000724722 | SCV000057386 | uncertain significance | not provided | 2014-03-10 | criteria provided, single submitter | clinical testing | The M82V missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Server reports M82V was not observed in approximately 6,200 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations, and M82V is also not present in the 1000 Genomes Database. M82V is located at a conserved position within the N-SH2 domain of the SHP2 protein encoded by PTPN11. This domain is the first of two sites involved in switching the protein between its inactive and active conformations. Missense mutations at nearby positions (Q79P, Q79R, D106A) have been reported previously in association with Noonan syndrome. However, the M82V amino acid change is conservative in that both Methionine and Valine are uncharged, non-polar amino acids, and multiple in-silico analysis models predict that M82V is a benign sequence change. Therefore, based on the currently available information, it is unclear whether M82V is a disease-causing mutation or a rare benign variant. The variant is found in NOONAN panel(s). |