ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.854T>C (p.Phe285Ser) (rs121918463)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000077862 SCV000057419 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The F285S variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2002; Essawi et al., 2013). Additionally, the variant has been observed to occur apparently de novo in patients at GeneDx and in a patient reported to ClinVar (ClinVar SCV000061325.4; Landrum et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016). F285S is a non conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same residue (F285I/L/C) and in nearby residues (I282V/M) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077862 SCV000058300 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037663 SCV000061325 pathogenic Noonan syndrome 2012-08-16 criteria provided, single submitter clinical testing The p.Phe285Ser variant in PTPN11 has been reported in the literature in several individuals with the clinical features of Noonan syndrome, and has been shown t o have arisen as a de novo event in some of these individuals (Aoki 2008, Tartag lia 2006, Kosaki 2002, Park 2012, Essawi 2013, LMM data). It was absent from lar ge population studies. In addition, several other amino acid changes at this pos ition (p.Phe285Cys, p.Phe285Leu) have also been reported in individuals with Noo nan spectrum features. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner.
Blueprint Genetics RCV000037663 SCV000188822 pathogenic Noonan syndrome 2015-02-25 criteria provided, single submitter clinical testing
Invitae RCV000458650 SCV000549994 pathogenic Rasopathy 2019-09-09 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 285 of the PTPN11 protein (p.Phe285Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (rs121918463, ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome (PMID: 11992261, 18470943, 24183200, 19020799, 15240615). In some of these cases, this variant was de novo in the affected individual (PMID: 23321623, 21106241). ClinVar contains an entry for this variant (Variation ID: 13335). An experimental study has shown that this missense change slightly increases PTPN11 basal activity and sensitivity to ligand stimulation in vitro (PMID: 27030275). Two different missense substitutions at this codon (p.Phe285Cys, p.Phe285Leu) have been determined to be pathogenic (PMID: 16358218, 18470943, 11992261). This suggests that the phenylalanine residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000458650 SCV000920100 pathogenic Rasopathy 2018-09-24 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.854T>C (p.Phe285Ser) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246952 control chromosomes (gnomAD). The variant, c.854T>C, has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Tartaglia_2006, Kosaki_2002, Croonen_2013, Lee_2011, ssawi_2013, Bertola_2006, Prontera_2013). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. In addition, other missense mutations at this position, Phe285Cys and Phe285Leu, have been reported to be pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000014263 SCV000034512 pathogenic Noonan syndrome 1 2002-08-01 no assertion criteria provided literature only
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014263 SCV000143818 not provided Noonan syndrome 1 no assertion provided not provided
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000037663 SCV000206709 pathogenic Noonan syndrome 2008-10-09 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000077862 SCV000207658 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Center for Advanced Molecular Diagnostics, Cytogenetics Laboratory,Brigham and Women's Hospital RCV000190417 SCV000239863 pathogenic Early T cell progenitor acute lymphoblastic leukemia no assertion criteria provided clinical testing Activating PTPN11 mutation found in ETP-ALL, juvenile myelomonocytic leukemia, and Noonan syndrome

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