ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.774G>T (p.Glu258Asp) (rs397516809)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037656 SCV000061318 likely pathogenic Noonan syndrome 2015-02-23 criteria provided, single submitter clinical testing The p.Glu258Asp variant in PTPN11 has been reported in 3 Dutch individuals with Noonan syndrome (Jongmans 2011) and identified by our laboratory in 1 Ashkenazi Jewish adult with a clinical diagnosis of Noonan syndrome (LMM, unpublished data ). It was absent from large population studies. Computational prediction tools a nd conservation analysis suggest that this variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, although additional studies are required to fully establish its clinical sig nificance, the p.Glu369Asp variant is likely pathogenic.
GeneDx RCV000159049 SCV000208991 likely pathogenic not provided 2021-02-01 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: 21407260)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002142 SCV001159997 pathogenic not specified 2018-10-19 criteria provided, single submitter clinical testing The PTPN11 c.774G>T; p.Glu258Asp variant (rs397516809) has been described in at least one individual affected with Noonan syndrome (Jongmans 2011). It is reported as pathogenic/likely pathogenic in ClinVar (Variation ID: 44613) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 258 is moderately conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, the crystal structure demonstrates that Glu258 is important in stabilizing an inhibitory interaction of two protein domains (Hof 1998), and several nearby variants have been described in individuals affected with Noonan syndrome (Binder 2005, Musante 2003, Pannone 2017). Based on available information, this variant is considered pathogenic. REFERENCES Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. Musante L et al. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet. 2003 Feb;11(2):201-6. Pannone L et al. Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome. Hum Mutat. 2017 Apr;38(4):451-459.

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