ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1504T>A (p.Ser502Thr) (rs121918458)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212897 SCV000057448 pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing The S502T variant has been published as an assumed de novo pathogenic variant in a patient diagnosed with Noonan syndrome (Niihori et al., 2005). Another patient who harbored this variant developed leukocytosis and neuroblastoma at 3 months and 6 months of age respectively (Kondoh et al., 2003). In vitro functional studies demonstrated that the presence of the S502T variant resulted in a significant increase in phosphatase activity over wild-type (Niihori et al., 2005). The S502T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S502T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this residue (S502A, S502L) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). Therefore, this variant is pathogenic.
Center for Human Genetics, Inc RCV000014260 SCV000782254 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212897 SCV000884432 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing The p.Ser502Thr variant (rs121918458) has been reported in multiple patients diagnosed with Noonan syndrome (Niihori 2005, Tartaglia 2006, van Trier 2016, Yoshida 2004), and reported as a presumed de-novo variant (Joyce 2016, Kondoh 2003, Maheshwari 2002). The serine residue is located in the phospho-tyrosine phosphatase domain of PTPN11, and interacts with the N-SH2 domain to mediate regulatory inhibition (Hof 1998). Functional characterization of the p.Ser502Thr protein indicates increased catalytic activity of the phosphatase (Niihori 2005), consistent with the established disease mechanisms of Noonan syndrome.
Blueprint Genetics RCV000212897 SCV000927150 pathogenic not provided 2017-02-14 criteria provided, single submitter clinical testing
OMIM RCV000014260 SCV000034508 pathogenic Noonan syndrome 1 2003-07-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000033543 SCV000204062 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2015-09-29 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156995 SCV000206719 pathogenic Noonan syndrome 2012-01-30 no assertion criteria provided clinical testing

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