rs397507520

chr12-112453279-G-Cchr12-112453279-G-T

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: PTPN11 NM_002834 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:39
• Conservation: PhyloP100: 3.63

ACMG classification

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
PTPN11	NM_002834.5	c.417G>C	p.Glu139Asp	missense_variant	4/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.417G>C	p.Glu139Asp	missense_variant	4/16	1	NM_002834.5	A1

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

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:

Submissions by phenotype

Noonan syndrome 1 Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Mar 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Mar 24, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Klinikum rechts der Isar	Dec 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based 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 submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 29, 2022	ACMG classification criteria: PS2 strong, PS3 strong, PS4 strong, PM2 moderated, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	The 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 submitter	clinical testing	GeneDx	Jan 10, 2022	Published 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 provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Sep 01, 2020	This 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 submitter	clinical testing	PerkinElmer Genomics	Jul 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 05, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	Criteria applied: PS1, PM2, PS4:Moderate, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 10, 2020	PS3, PS4, PM2, PP1, PP5 -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	Same 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 panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	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, 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 provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2022	This 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 submitter

clinical testing

Ambry Genetics

Jun 05, 2014

- -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2018

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. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 14, 2020

- -

Noonan syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 28, 2017

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. -

Ptosis;C0221356:Brachycephaly;C0557874:Global developmental delay;C2051831:Pectus excavatum;C4551563:Microcephaly Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 17, 2021

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 21, 2017

- -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 07, 2023

- -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 07, 2023

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2021

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;70:1555-63; 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 submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Aug 22, 2020

This 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

Other links and lift over

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