Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212895 | SCV000057418 | likely pathogenic | not provided | 2024-10-28 | criteria provided, single submitter | clinical testing | Identified in patients with Noonan-spectrum disorders referred for genetic testing at GeneDx and in published literature (PMID: 16358218); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24803665, 19120036, 29493581, 16358218, 12161469) |
Laboratory for Molecular Medicine, |
RCV000037664 | SCV000061326 | pathogenic | Noonan syndrome | 2017-02-28 | criteria provided, single submitter | clinical testing | The p.Phe285Cys variant in PTPN11 has been reported in two individuals with clin ical features of Noonan syndrome and was reported to segregate with clinical fea tures in one family (Tartaglia 2006, Nystrom 2009). In addition, this variant ha s been identified by our laboratory in 5 individuals with clinical features of N oonan syndrome and segregated with clinical features in one family (3 meioses; L MM data). This variant was also absent from large population studies. Furthermor e, other amino acid changes at this position (p.Phe285Ser and p.Phe285Leu) have been reported in individuals with Noonan syndrome, suggesting that changes to th is position may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome based on its occurrence in multiple affected individuals, segregation studies, and localization in a mutation hotsp ot. |
Labcorp Genetics |
RCV000033513 | SCV000253881 | pathogenic | RASopathy | 2023-11-08 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 285 of the PTPN11 protein (p.Phe285Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 16358218; ClinVarRCV000037664). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40533). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18470943, 18678287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |