ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.417G>T (p.Glu139Asp) (rs397507520)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212894 SCV000057395 pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing The E139D variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2002). The E139D 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 E139D 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. Functional studies have demonstrated that the E139D variant alters the specificity of the C-SH2 domain, making it similar to that of the N-SH2 domain, ultimately leading to functional disregulation (Martinelli et al., 2008). The E139D variant resulting from a different nucleotide substitution (c.417 G>C) has been observed at GeneDx and reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014).
Invitae RCV000033490 SCV000549981 pathogenic Rasopathy 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 139 of the PTPN11 protein (p.Glu139Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 11992261, 16358218). ClinVar contains an entry for this variant (Variation ID: 40512). Several studies have reported that this missense change leads to structural changes and increased activation of the PTPN11 protein (PMID: 18372317, 23584145, 15987685, 24628801). A different variant (c.417G>C) giving rise to the same protein effect observed here (p.Glu139Asp) has been reported in several patients affected with Noonan syndrome (PMID: 11992261, 22315187, 19020799, 17339163), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824742 SCV000061309 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2015-01-16 criteria provided, single submitter clinical testing The p.Glu139Asp (c.417G>T) variant in PTPN11 has been identified in 3 individua ls with Noonan syndrome (Tartaglia 2002, LMM unpublished data). It has not been identified in large population studies. In addition, another nucleotide change (c.417G>C) that results in the same amino acid change has also been reported in at least 10 individuals with Noonan syndrome, 1 individual with Noonan syndrome and acute lymphoblastic leukemia (ALL), 1 individual with Juvenile myelomonocyti c leukemia (JMML), and 1 individual with Noonan syndrome that developed ALL and JMML (Musante 2002, Loh 2004, Bertola 2006, Chan 2006, Hung 2007, Karow 2007, Ko 2008, Derbent 2010, Jongmans 2011, Pauli 2012, Timeus 2013). This variant has b een reported to show both familial segregation and to have occurred de novo (Jon gmans 2005, Houweling 2010). In summary, this variant meets our criteria to be c lassified as pathogenic (http://www.partners.org/personalizedmedicine/LMM).

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