ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.854T>G (p.Phe285Cys)

dbSNP: rs121918463
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212895 SCV000057418 likely pathogenic not provided 2021-12-07 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24803665, 16358218, 19120036, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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.
Invitae 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.