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rs397507510

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_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 0.0000012 in 832,392 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D61A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

10
7
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 9.99
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr12-112450362-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, PTPN11
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 id is 40495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450361-G-A is described in Lovd as [Likely_pathogenic]. Variant chr12-112450361-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.181G>A p.Asp61Asn missense_variant 3/16 ENST00000351677.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.181G>A p.Asp61Asn missense_variant 3/161 NM_002834.5 A1Q06124-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000120
AC:
1
AN:
832392
Hom.:
0
Cov.:
31
AF XY:
0.00000260
AC XY:
1
AN XY:
384386
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:
0.00000131
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:22
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 18, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 29, 2022Published 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) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsFeb 28, 2018- -
Pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoNov 15, 2019DNA 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. -
Pathogenic, no assertion criteria providedclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 15, 2015- -
Pathogenic, criteria provided, single submitterclinical testingCentro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de SaludFeb 02, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMar 28, 2023PP2, PM1, PM2_supporting, PM5_strong, PS3, PS4 -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Noonan syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinOct 17, 2022ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PP2 supporting -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000372703.2, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asp61His, p.Asp61Tyr, p.Asp61Val, p.Asp61Gly, Asp61Ala) has been reported as pathogenic (PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.648, 3Cnet: 0.972, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 09, 2022- -
PTPN11-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 10, 2023The 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. -
LEOPARD syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 09, 2022- -
Metachondromatosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsAug 09, 2022- -
LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoAug 01, 2017PTPN11 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). -
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 27, 2016The 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. -
Noonan syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 06, 2019Variant 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. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 16, 2019The 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. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoDec 22, 2021PTPN11 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). -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenAug 01, 2018- -
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 26, 2024This 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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Uncertain
0.82
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
Cadd
Pathogenic
32
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Benign
1.4
L;L;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Uncertain
-4.1
D;D;.;.
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0010
D;D;.;.
Sift4G
Uncertain
0.0090
D;D;.;D
Polyphen
1.0
D;D;.;.
Vest4
0.89
MutPred
0.91
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.94
MPC
1.9
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.93
gMVP
0.67

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

LitVar

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

Other links and lift over

dbSNP: rs397507510; hg19: chr12-112888165; COSMIC: COSV61006164; COSMIC: COSV61006164; API