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rs397507520

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_StrongPM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834(PTPN11):c.417G>C(p.Glu139Asp) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (β˜…β˜…β˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E139G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Failed GnomAD Quality Control

Consequence

PTPN11
NM_002834 missense

Scores

6
10
3

Clinical Significance

Pathogenic reviewed by expert panel P:39

Conservation

PhyloP100: 3.63

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 25 ACMG points.

PS1
?
Transcript NM_002834 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 40512
PM1
?
In a strand (size 5) in uniprot entity PTN11_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_002834
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr12-112453278-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2095543. Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, PTPN11
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
?
Variant 12:112453279-G>C is Pathogenic according to our data. Variant chr12-112453279-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40513. Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-112453279-G-C is described in Lovd as [Likely_pathogenic]. Variant chr12-112453279-G-C is described in Lovd as [Pathogenic]. Variant chr12-112453279-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.417G>C p.Glu139Asp missense_variant 4/16 ENST00000351677.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.417G>C p.Glu139Asp missense_variant 4/161 NM_002834.5 A1Q06124-2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152190
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000159
AC:
1
AN:
628568
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
342414
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000286
Gnomad4 OTH exome
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:39
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Noonan syndrome 1 Pathogenic:12
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsMar 01, 2018- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 07, 2023- -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CitySep 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn-- -
Pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaMar 24, 2015- -
Likely pathogenic, criteria provided, single submitterclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMar 14, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Klinikum rechts der IsarDec 16, 2022- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 19, 2020Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis and LEOPARD syndrome have been associated with a loss of function variants, whereas Noonan syndrome is caused by gain of function variants (OMIM). (N) 0107 - This gene is known to be associated with autosomal dominant Noonan Syndrome. Autoimmune disorders, in particular autoimmune hepatitis, have been reported as a rare association of Noonan syndrome (PMIDs: 22488759; 25595571). (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to asparagine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif. The variant is located in the C-terminal SH2 domain (NCBI conserved domain). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar (reviewed by expert panel). (P) 1002 - Moderate functional evidence supporting abnormal protein function. COS-1 cells transfected with the mutant p.(Glu139Asp) cDNA demonstrated higher phosphatase activity compared to WT cDNA when stimulated with bisphosphoryl tyrosine-based activation motif (BTAM) peptide (PMID: 16358218). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinOct 29, 2022ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM2 moderated, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submittercase-controlGenetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital-- -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021The variant has been previously reported as de novoo in at least four similarly affected unrelated individuals (PMID: 22315187, 17020470, 11992261, 3billion dataset, PS2, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15987685, 18372317, 23584145, PS3). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.769, 3Cnet: 0.960, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:11
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 10, 2022Published functional studies demonstrate the p.(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 (Keilhack et al., 2005; Martinelli et al., 2008); Not observed in large population cohorts (gnomAD); 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 (HGMD); This variant is associated with the following publications: (PMID: 11992261, 23584145, 26377682, 26855057, 23321623, 20308328, 24628801, 18372317, 25585602, 12634870, 16358218, 24072241, 15710330, 22315187, 24803665, 28363362, 26918529, 21407260, 19020799, 17339163, 29500832, 21901340, 30293248, 30417923, 30050098, 30410095, 29907801, 31219622, 31560489, 32164556, 32581362, 32978145, 33619735, 34134972, 29493581, 15987685) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncSep 01, 2020This variant occurs de novo in an individual tested at Athena Diagnostics and in published literature (PMID: 21706501). Furthermore, it has been reported in multiple unrelated symptomatic individuals (PMID: 30417923, 31560489, 28363362, 29907801, 19020799). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 18372317).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitterclinical testingPerkinElmer GenomicsJul 08, 2021- -
Pathogenic, no assertion criteria providedclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 15, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareOct 05, 2015- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022Criteria applied: PS1, PM2, PS4:Moderate, PP2, PP3 -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsSep 05, 2017- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 17, 2015- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 10, 2020PS3, PS4, PM2, PP1, PP5 -
Noonan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingDASAMar 05, 2022Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (ClinVar ID: 40512 - c.417G>T;p.(Glu139Asp)) PS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23584145; 15987685) - The c.417G>C;p.(Glu139Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40513; PMID: 22315187; PMID: 17020470; PMID: 11992261) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2) - PM1. This variant is not present in population databases (rs397507520- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 03, 2017The 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, http://exac.broadinstitute.org). 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. -
RASopathy Pathogenic:2
Pathogenic, no assertion criteria providedclinical testingBaylor Genetics-Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitterclinical testingInvitaeOct 25, 2022This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 139 of the PTPN11 protein (p.Glu139Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11992261, 17339163, 19020799, 22315187). ClinVar contains an entry for this variant (Variation ID: 40513). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18372317, 23584145, 24628801). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 05, 2014- -
Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 07, 2018The 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. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 14, 2020- -
Noonan syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 28, 2017Variant 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. -
Ptosis;C0221356:Brachycephaly;C0557874:Global developmental delay;C2051831:Pectus excavatum;C4551563:Microcephaly Pathogenic:1
Pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of Cambridge-- -
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 01, 2017- -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 17, 2021- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 21, 2017- -
Metachondromatosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 07, 2023- -
LEOPARD syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 07, 2023- -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 16, 2021The 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;70:1555-63; Jongmans M et al. Horm Res. 2004;62 Suppl 3:56-9; Bakker M. Prenat Diagn. 2011;31:833-40; Nair S et al. Pediatr Blood Cancer. 2015;62:1084-6; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337; Athota JP et al. BMC Med Genet, 2020 03;21:50). Some individuals with this alteration were also reported to develop leukemia (JPauli S et al. Am J Med Genet. 2012;158A:652-8; Park HD et al. Ann Hematol. 2012;91:511-7). In addition, this alteration was determined to be the result of de novo mutation or germline mosaicism through whole exome sequencing in 3 families with isolated cases of Noonan syndrome (Ambry internal data). 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, this alteration is interpreted as a disease-causing mutation. -
PTPN11 Related Disorders Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San DiegoAug 22, 2020This variant has been previously reported as a de novo or heterozygous change in patients with PTPN11-related disorders (PMID: 11992261, 22315187, 19020799, 17339163, 32164556, 28363362). Functional studies have reported that the variant alters the specificity of the C-SH2 domain ultimately leading to functional dysregulation and increased PTPN11 activation (PMID: 18372317, 23584145). It is absent from the gnomAD population database and thus is presumed to be rare. The c.417G>C (p.Glu139Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.417G>C (p.Glu139Asp) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
Cadd
Uncertain
25
Dann
Uncertain
1.0
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.67
T;T;T;T
M_CAP
Uncertain
0.090
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
0.44
D
MutationAssessor
Benign
1.1
L;L;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.4
N;D;.;.
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0090
D;D;.;.
Sift4G
Uncertain
0.015
D;D;.;D
Polyphen
0.99
D;D;.;.
Vest4
0.78
MutPred
0.90
Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);
MVP
0.98
MPC
1.8
ClinPred
0.95
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.71
gMVP
0.61

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397507520; hg19: chr12-112891083; COSMIC: COSV61009400; COSMIC: COSV61009400;