rs397507510

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.181G>A(p.Asp61Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24

Conservation

PhyloP100: 9.99

Publications

170 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 23 ACMG points.

PS1

Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002834.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112450361-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228392.

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, 0.948

PP5

Variant 12-112450361-G-A is Pathogenic according to our data. Variant chr12-112450361-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 40495.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.181G>A	p.Asp61Asn	missense_variant	Exon 3 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.181G>A	p.Asp61Asn	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1 link	c.181G>A	p.Asp61Asn	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460946

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111210

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Feb 28, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 29, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate the variant results in significantly increased activation of the PTPN11 protein compared to wild type (Niihori et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 32164556, 11992261, 25097206, 26242988, 24803665, 27521173, 26817465, 12634870, 24150203, 28607217, 30417923, 26918529, 30050098, 29907801, 31560489, 30755392, 33300679, 33502061, 32719394, 27535533, 15834506, 9491886, 16053901, 29493581)

Mar 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP2, PM1, PM2_supporting, PM5_strong, PS3, PS4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 15, 2019

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.181G>A, in exon 3 that results in an amino acid change, p.Asp61Asn. This sequence change has not been reported in population databases (gnomAD, ExAC). The p.Asp61Asn change has been identified in several individuals with Noonan syndrome (PMIDs: 11992261, 26242988, 27521173). Other variants at the same amino acid residue (p.Asp61Ala, p.Asp61His, p.Asp61Gly) have also been reported as pathogenic for Noonan syndrome (PMIDs: 19927903, 11704759, 20112233). Functional studies showed that PTPN11 phosphatase activity increased in the presence of this variant (PMID: 15834506). The p.Asp61Asn change affects a highly conserved amino acid residue located in the N-SH2 domain of the PTPN11 protein, which is known to be functional. In-silico pathogenicity prediction tools (PolyPhen2, Align GVGD, REVEL) predict this variant to be deleterious.

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 18, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 02, 2022

Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Noonan syndrome 1

Pathogenic:4

Oct 17, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PP2 supporting

Aug 09, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 25, 2025

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.65 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)].The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040495 / PMID: 11992261 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Asp61Ala, p.Asp61Gly, p.Asp61His, p.Asp61Tyr, p.Asp61Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013330, VCV000040494, VCV000040496, VCV000179221, VCV000228392 / PMID: 11704759, 19927903, 20112233, 34358384 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Centre for Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.181G>A change in exon 3 that results in an amino acid change p.Asp61Asn that affects a highly conserved amino acid residue located in the N-SH2 domain of the PTPN11 protein. This change identified in several individuals with Noonan syndrome and many in-silico tools predict a damaging effect of the variant on protein function.

LEOPARD syndrome 1;C4551602:Noonan syndrome 1

Pathogenic:2

Dec 13, 2022

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.181G>A variant in PTPN11 has previously been reported in individuals with Noonan syndrome [PMID: 11992261, 15834506, 16358218, 22847776, 24150203, 26242988, 27521173, 29907801, 26918529, 32164556] and has been deposited in ClinVar [ClinVar ID: 40495] as Pathogenic by multiple submitters. The c.181G>A variant is observed in 1 allele (~0.00065% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.181G>A variant in PTPN11 is located in exon 3 of this 16-exon gene and predicted to replace an evolutionarily conserved aspartate amino acid with asparagine at position 61 in the N-SH2 domain of the encoded protein [PMID: 24628801]. In vitro functional studies demonstrated increased phosphatase activity in fibroblast cells carrying c.181G>A variant [PMID: 15834506]. Other missense variants affecting the same p.(Asp61) residue have been reported in the literature (p.Asp61Gly) [PMID: 26918529] and ClinVar [ClinVar IDs: 13330] in individuals with Noonan syndrome. Based on available evidence this de novo c.181G>A p.(Asp61Asn) variant identified in PTPN11 is classified here as Pathogenic for Noonan syndrome 1.

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTPN11 NM_002834.3 exon3 p.Asp61Asn (c.181G>A): This variant has been reported in the literature in at least 7 individuals with Noonan syndrome, including some individuals with juvenile myelomonocytic leukemia (JMML) (Tartaglia 2002 PMID:11992261, Strullu 2014 PMID:25097206, Joyce 2016 PMID:26242988, Van Trier 2016 PMID:27521173). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:40495). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant occurs within the N-SH2/PTP interaction domain, a critical region for the function of this gene, and increases the likelihood that this variant is damaging (Tartaglia 2002 PMID: 11992261. Strullu 2014 PMID:25097206). Several variants at this codon (p.Asp61Gly, p.Asp61Ala, p.Asp61His) have been reported in association with Noonan syndrome and as a de novo, suggesting that this codon may be particularly important. In summary, this variant is classified as pathogenic based on the data above (number of probands, absence from controls, presence in functionally critical region).

RASopathy

Pathogenic:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 61 of the PTPN11 protein (p.Asp61Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15834506, 16358218, 24150203, 26242988, 27521173). ClinVar contains an entry for this variant (Variation ID: 40495). 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: 15834506). This variant disrupts the p.Asp61 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15273746, 16358218, 23321623, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Aug 06, 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.181G>A (p.Asp61Asn) results in a 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 252048 control chromosomes. c.181G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Metachondromatosis

Pathogenic:1

Aug 09, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LEOPARD syndrome 1

Pathogenic:1

Aug 09, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTPN11-related disorder

Pathogenic:1

Aug 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PTPN11 c.181G>A variant is predicted to result in the amino acid substitution p.Asp61Asn. This variant has been reported in multiple individuals with Noonan syndrome (Tartaglia et al. 2002. PubMed ID: 11992261; Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218; Joyce et al. 2016. PubMed ID: 26242988). Additionally, different amino acid substitutions affecting the same amino acid (p.Asp61His, p.Asp61Ala, p.Asp61Gly) and nearby amino acids (p.Gly60Ser, p.Gly60Cys, p.Gly60Ala, p.Gly60Val, p.Tyr62Asn, p.Tyr62Asp, p.Tyr62Cys) have been reported as pathogenic (Human Gene Mutation Database). This variant has been interpreted as pathogenic by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/40495/). This variant is interpreted as pathogenic.

Noonan syndrome

Pathogenic:1

May 27, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp61Asn variant in PTPN11 has been previously reported in >20 individuals with clinical features of Noonan syndrome (Tartaglia 2002, Tartaglia 2006, Stru llu 2014, LMM data), and at least 4 of whom also had a myoproliferative disorder including juvenile myelomonocytic leukemia (JMML; Loh 2004, Strullu 2014). It i s also absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Asp61Asn variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, this variant meets our criteria to be classified as pathogenic for No onan syndrome in an autosomal dominant manner based upon prevalence in affected probands and absence from controls.

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

Pathogenic:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Pathogenic:1

May 16, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D61N pathogenic mutation (also known as c.181G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 181. The aspartic acid at codon 61 is replaced by asparagine, an amino acid with highly similar properties. This pathogenic variant has been reported in multiple individuals with confirmed or suspected Noonan syndrome, including multiple de novo cases (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ferreira LV et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5156-60; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Derbent M et al. Am. J. Med. Genet. A, 2010 Nov;152A:2768-74; Lee BH et al. J. Pediatr., 2011 Dec;159:1029-35; Pasmant E et al. Am. J. Med. Genet. A, 2012 Sep;158A:2290-1; Strullu M et al. J. Med. Genet., 2014 Oct;51:689-97; van Trier DC et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jun;79:874-8; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Joyce S et al. Eur. J. Hum. Genet., 2016 May;24:690-6). This variant is located in the NSH2 domain, which interacts with the PTP domain to regulate switching of the resulting protein between its inactive and active conformations (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90) and other disease-causing variants at the same codon (p.D61G, p.D61H, p.D61A) have been described (Strullu M et al. J. Med. Genet., 2014 Oct;51:689-97; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Aug 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

0.99

CardioboostCm

Uncertain

0.82

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;.;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.87

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Benign

1.4

L;L;.;L

PhyloP100

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-4.1

D;D;.;.

Sift

Uncertain

0.0010

D;D;.;.

Sift4G

Uncertain

0.0090

D;D;.;D

Vest4

0.89

ClinPred

1.0

GERP RS

5.9

Varity_R

0.93

gMVP

0.67

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over