ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.854T>G (p.Phe285Cys) (rs121918463)

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Total submissions: 3
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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, Partners HealthCare 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 2015-06-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 285 of the PTPN11 protein (p.Phe285Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is reported in multiple individuals affected with Noonan syndrome (PMID: 16358218; ClinVar: RCV000037664) and is not present in population databases (Exac). In two independent families, it was found to co-segregate with disease (MID: 16358218; ClinVar: RCV000037664). This missense change is located within a functionally conserved PTP domain of the PTPN11 protein (PMID: 11992261) and a high percentage of previously reported missense mutations have been found within this domain (PMID: 18470943). In addition, three different missense substitutions at this codon (p.Phe285Ser, p.Phe285Leu, p.Phe285Ile) have been reported in individuals with Noonan syndrome (PMID: 18470943, 18678287). These observations indicate that the Phe285 residue is important for PTPN11 function and a missense change at this location likely affects protein function, although experiments have not been done to test these predictions. In summary, this is rare missense change that is not seen in the general population, co-segregates with disease in individuals with Noonan syndrome, and is expected to disrupt protein function. For these reasons, it has been classified as Pathogenic.

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