Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000033472 | SCV000057377 | pathogenic | not provided | 2024-04-11 | criteria provided, single submitter | clinical testing | Identified in probands with ultrasound findings consistent with PTPN11-related RASopathy (PMID: 18759865, 26918529); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30355600, 15928039, 12717436, 26918529, 18759865) |
Laboratory for Molecular Medicine, |
RCV000037635 | SCV000061297 | likely pathogenic | Noonan syndrome | 2012-09-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003103718 | SCV000698069 | pathogenic | Noonan syndrome with multiple lentigines | 2023-01-26 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.214G>C (p.Ala72Pro) results in a non-conservative amino acid change located in the N-terminal Src homology 2 (N-SH2) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251056 control chromosomes. c.214G>C has been reported in the literature in individuals affected with Noonan Syndrome (example, PMID: 18759865, 26918529). At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 16358218). The most pronounced variant effect results in statistically significant higher phosphatase activities basally and after stimulation with BTAM peptide consistent with a gain of function mechanism of disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Blueprint Genetics | RCV000033472 | SCV000927439 | pathogenic | not provided | 2017-10-16 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001852674 | SCV002300216 | likely pathogenic | RASopathy | 2022-07-01 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 72 of the PTPN11 protein (p.Ala72Pro). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 18759865). 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. This variant disrupts the p.Ala72 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12161469, 26918529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 40500). |