rs397507501

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_002834.5(PTPN11):c.124A>G(p.Thr42Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T42S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 7.31

Publications

38 publications found

Variant links:

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

PTPN11 Gene-Disease associations (from GenCC):

LEOPARD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
metachondromatosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112446385-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3573673.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

PP5

Variant 12-112446385-A-G is Pathogenic according to our data. Variant chr12-112446385-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.124A>G	p.Thr42Ala	missense_variant	Exon 2 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:6

Lifecell International Pvt. Ltd

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous Missense variant c.124A>G in Exon 2 of the PTPN11 gene that results in the amino acid substitution p.Thr42Ala was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has previously reported for patients with RASopathies by Digilio MC, et, al., 2012. Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al.,2008.) ClinVar has also classified this variant as Pathogenic (Variant ID: 40482). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Nov 12, 2021

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The de novo c.124A>G (p.Thr42Ala) variant identified in the PTPN11 gene substitutes a moderatley conserved Threonine for Alanine at amino acid 42/594 (exon 2/16). This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. The variant is predicted deleterious by multiple in silico prediction tools (CADD score = 25.3, REVEL score = 0.794). This variant is reported in ClinVar as Pathogenic (VarID: 40482), and has been reported in many individuals in the literature with Noonan syndrome [PMID:11992261, 15001945, 12960218, 29988639, 31560489, other]. Functional studies suggest that the p.Thr42Ala variant promotes increased phosphopeptide-binding affinity [PMID:18372317]. Given its presence de novo, absence in population databases, presence in multiple affected individuals in the literature, and functional studies suggesting a significant increase in phosphopeptide binding affinity, the c.124A>G (p.Thr42Ala) variant identified in the PTPN11 gene is reported as Pathogenic. -

Jun 03, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Molecular Genetics, Centre for Human Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 27, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense c.124A>G(p.Thr42Ala) variant in PTPN11 gene has been reported previously in multiple individuals affected with Noonan syndrome (Tamura A, et al., 2018; Digilio MC, et al., 2013; Tartaglia M, et al., 2006). Functional studies showed that this variant results in increased phosphopeptide binding affinity and dephosphorylation supporting the proposed molecular mechanism of its pathogenicity (Martinelli S, et al., 2008). The p.Thr42Ala variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The reference amino acid change at this position on PTPN11 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 42 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Jun 21, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005; Muller et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16358218, 30417923, 30050098, 18372317, 23584145, 15987685, 25425531, 24803665, 21590266, 17661820, 28483241, 11992261, 22781091, 29988639, 29907801, 31219622, 31560489, 32164556, 31936901, 32668055, 29493581, 33258288, 32786180) -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome

Pathogenic:3

Jan 27, 2012

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 19, 2015

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Thr42Ala variant in PTPN11 has been reported in 10 individuals in the litera ture (Tartaglia 2002, Sarkozy 2003, Zenker 2004, Lee 2007, Shaw 2007, Martinelli 2008, Digilio 2012) and one individual in our laboratory with clinical features of Noonan syndrome. This variant was reported to have occurred de novo in at le ast one of these individuals (Digilio 2012). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

RASopathy

Pathogenic:2

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 42 of the PTPN11 protein (p.Thr42Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15001945, 16358218, 17661820, 21590266, 22781091). ClinVar contains an entry for this variant (Variation ID: 40482). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18372317, 23584145). For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2019

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PTPN11 c.124A>G (p.Thr42Ala) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246614 control chromosomes (gnomAD). c.124A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome, including de novo cases (Tartaglia_2002, Sarkozy_2003, Zenker_2004, Lee_2007, VanTrier_2015, Tamura_2018, Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. This variant exhibits increased affinity for mono-Tyr(P) peptide and phosphopeptide (Keilhack_2005 and Martinelli_2008), which is believed to be one of the mechanisms of SHP2's functional dysregulation. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

PTPN11-related disorder

Pathogenic:1

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PS4, PM2, PP3 -

Cardiovascular phenotype

Pathogenic:1

May 07, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T42A pathogenic mutation (also known as c.124A>G), located in coding exon 2 of the PTPN11 gene, results from an A to G substitution at nucleotide position 124. The threonine at codon 42 is replaced by alanine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Noonan syndrome; in at least one individual, it was determined to be de novo (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Lee ST et al. Clin. Genet., 2007 Aug;72:150-5; van Nierop JWI et al. Int. J. Pediatr. Otorhinolaryngol., 2017 Jun;97:228-234). In an assay testing PTPN11 function, this variant showed a functionally abnormal result (Martinelli S et al. Hum. Mol. Genet., 2008 Jul;17:2018-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation for PTPN11-related RASopathy; however, it is unlikely to be causative of metachondromatosis. -

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

Pathogenic:1

Sep 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Dec 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Uncertain

0.10

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;.;D

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Uncertain

0.038

MutationAssessor

Benign

0.72

N;N;.;N

PhyloP100

7.3

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.4

D;D;.;.

REVEL

Pathogenic

0.79

Sift

Benign

0.10

T;T;.;.

Sift4G

Benign

0.077

T;T;.;T

Polyphen

0.60

P;P;.;.

Vest4

0.82

MutPred

0.84

Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);

MVP

0.95

MPC

1.2

ClinPred

0.97

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.81

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over