Submissions for variant NM_002834.5(PTPN11):c.417G>T (p.Glu139Asp)

dbSNP: rs397507520

Total submissions: 8

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).
Laboratory for Molecular Medicine, Mass General Brigham 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T) variant in PTPN11 has been identified in 3 individua ls with Noonan syndrome (Tartaglia 2002, LMM unpublished data).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).
Invitae	RCV000033490	SCV000549981	pathogenic	RASopathy	2021-07-22	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). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTPN11 protein function (PMID: 18372317, 23584145, 20308328). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 16358218, 19020799, 17339163). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40512).
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000995621	SCV001149900	pathogenic	Noonan syndrome 1	2018-06-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267275	SCV001445456	pathogenic	Inborn genetic diseases	2017-12-21	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000995621	SCV002559210	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212894	SCV001741834	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212894	SCV001954780	pathogenic	not provided		no assertion criteria provided	clinical testing