ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp) (rs397507520)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521568 SCV000616373 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.417G>C (p.Glu139Asp) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients and at least 5 other independent occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PS4; GeneDx, Baylor, BC Children's internal data; SCV000057396.11, SCV000196664.1, SCV000803709.1; GTR Lab ID: 26957, 1006, 249401 PMID: 22315187, 17020470, 11992261). This variant was absent from large population studies (PM2; ExAC, In vitro functional studies provide some evidence that the p.Glu139Asp variant may impact protein function (PS3; PMID: 23584145, 15987685, 18372317). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the c.417G>C (p.Glu139Asp) variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2, PP3.
GeneDx RCV000077858 SCV000057396 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing The E139D missense variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2002; Pauli et al. 2012). Subsequent 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 dysregulation (Martinelli et al., 2008). E139D has also been observed de novo in multiple individuals referred for testing at GeneDx. It is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Another nucleotide change (c.417 G>T) resulting in the same missense change has been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). Therefore, we consider this variant to be pathogenic
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824741 SCV000203936 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2018-12-07 criteria provided, single submitter clinical testing The p.Glu139Asp variant in PTPN11 has been identified in many individuals with c linical features of Noonan syndrome, one individual with clinical features of No onan syndrome and acute lymphoblastic leukemia, and one individual with juvenile myelomonocytic leukemia (Ko 2008, Karow 2007, Tartaglia 2002, Chan 2006, Loh 20 04, Bertola 2006, Hung 2007, Lo 2009, LMM unpublished data). This variant has be en reported to have segregated in familial cases and to have occurred de novo as well. In summary, this variant meets our criteria to be classified as pathogeni c. ACMG/AMP criteria applied: PS4, PM2, PM6, PP2, PP1.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157007 SCV000206733 pathogenic not specified 2017-01-21 criteria provided, single submitter clinical testing
Invitae RCV000033491 SCV000261087 pathogenic Rasopathy 2020-10-14 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 highly 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 been reported in the literature in multiple individuals affected with Noonan syndrome (PMID: 11992261, 22315187, 19020799, 17339163). Several studies have reported that this missense change leads to structural changes and increased activation of the PTPN11 protein (PMID: 18372317, 23584145, 15987685, 24628801). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000077858 SCV000265850 pathogenic not provided 2015-10-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077858 SCV000331038 pathogenic not provided 2015-08-17 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000357736 SCV000537744 pathogenic Noonan syndrome 1 2015-03-24 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515221 SCV000611307 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000585988 SCV000698076 pathogenic Noonan syndrome 3 2017-08-28 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.417G>C (p.Glu139Asp) variant causes a missense change involving the alteration of a conserved nucleotide located in the SH2 domain (IPR000980) (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies demonstrated the SHP2-D139E mutant to exhibit dramatically enhanced catalytic activation (3.5-fold), significant increase in phosphopeptide binding affinity of PTPN11, and approximately 4-fold increase in phosphatase activity after stimulation (Martinelli_2008, Tartaglia_2006). These findings from functional studies further corroborate the established molecular mechanism of disease (Gain of Function) attributed to pathogenic variants in the PTPN11 gene. The variant is absent in the control population datasets of ExAC in 121798 control chromosomes. This variant was reported in multiple patients with Noonan syndrome (Tartaglia_2006, Bertola_2006, Musante_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000617179 SCV000740052 pathogenic Cardiovascular phenotype 2016-10-24 criteria provided, single submitter clinical testing ​The p.E139D pathogenic mutation (also known as c.417G>C) is located in coding exon 4 of the PTPN11 gene. This alteration results from a G to C substitution at nucleotide position 417. The glutamic acid at codon 139 is replaced by aspartic acid. This alteration, and another nucleotide change resulting in the same amino acid substitution (c.417G>T), have been detected in multiple individuals reported to have Noonan syndrome or suspected Noonan syndrome, having been reported as occurring de novo in at least one case (Tartaglia M et al. Am J Hum Genet. 2002;70(6):1555-63; Jongmans M et al. Horm Res. 2004;62 Suppl 3:56-9; Bakker M. Prenat Diagn. 2011;31(9):833-40; Nair S et al. Pediatr Blood Cancer. 2015;62(6):1084-6). Some individuals with this alteration were also reported to develop leukemia (JPauli S et al. Am J Med Genet. 2012;158A(3):652-8; Park HD et al. Ann Hematol. 2012;91(4):511-7). In addition, this alteration was determined to be the result of a de novo mutation or germline mosaicism through whole exome sequencing in a family with an isolated case of Noonan syndrome in our clinical cohort. Furthermore, a functional study found this mutation altered the binding specificity of the C-SH2 domain so that they were similar to the N-SH2 domain and increased the phosphopeptide binding affinity (Martinelli S et al. Hum Mol Genet. 2008;17(13):2018-29). Based on the supporting evidence, p.E139D is interpreted as a disease-causing mutation.
Ambry Genetics RCV000623400 SCV000740906 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626830 SCV000747533 pathogenic Hypertrophic cardiomyopathy 2017-01-01 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000357736 SCV000803709 pathogenic Noonan syndrome 1 2018-03-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000077858 SCV000927395 pathogenic not provided 2017-09-05 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000357736 SCV000992397 pathogenic Noonan syndrome 1 criteria provided, single submitter case-control
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000357736 SCV000999337 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000077858 SCV001714424 pathogenic not provided 2020-11-10 criteria provided, single submitter clinical testing PS3, PS4, PM2, PP1, PP5
Genomics England Pilot Project,Genomics England RCV000357736 SCV001760295 likely pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Baylor Genetics RCV000033491 SCV000196664 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000077858 SCV000207655 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003604 SCV001161998 pathogenic Pectus excavatum; Global developmental delay; Brachycephaly; Ptosis; Microcephaly no assertion criteria provided research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000357736 SCV001469142 pathogenic Noonan syndrome 1 2020-09-10 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000077858 SCV001925408 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000077858 SCV001953247 pathogenic not provided no assertion criteria provided clinical testing

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