NM_002834.5:c.226G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The NM_002834.5(PTPN11):​c.226G>A​(p.Glu76Lys) 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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

15
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:2O:1

Conservation

PhyloP100: 9.99

Publications

290 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr12-112450408-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.921
PP5
Variant 12-112450406-G-A is Pathogenic according to our data. Variant chr12-112450406-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13336.We mark this variant Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTPN11NM_002834.5 linkc.226G>A p.Glu76Lys missense_variant Exon 3 of 16 ENST00000351677.7 NP_002825.3 Q06124-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkc.226G>A p.Glu76Lys missense_variant Exon 3 of 16 1 NM_002834.5 ENSP00000340944.3 Q06124-2
PTPN11ENST00000635625.1 linkc.226G>A p.Glu76Lys missense_variant Exon 3 of 15 5 ENSP00000489597.1 Q06124-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Jun 03, 2021
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported in published literature in patients with juvenile myelomonocytic leukemia (Kratz et al., 2005); Reported in published literature in association with somatic hematologic malignancies (Tartaglia et al., 2006); Published functional studies demonstrate a damaging effect on protein function and structure (Tartaglia et al., 2006; Gagne-Sansfaon et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22391158, 17177198, 29206716, 27582544, 15928039, 16358218, 9491886, 16053901, 11992261, 29493581, 27535533, 27783593, 23825065, 31222725, 15842656, 15385933, 14982869, 32697817, 12717436, 21930766, 19047918, 18470943, 14644997) -

Apr 09, 2018
Blueprint Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PTPN11: PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting -

Juvenile myelomonocytic leukemia Pathogenic:2
Jun 01, 2003
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Jun 21, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Glu76Lys variant in PTPN11 is an established pathogenic variant that has been identified as a somatic change in >40 individuals with JMML (Tartaglia 2003, Loh 2004, Kratz 2005, Tartaglia 2005, Aoki 2008, Yoshida 2009) and is absent from large population studies. In vitro and in vivo functional studies show that this variant has a strong gain of function impact (Tartaglia 2003, Loh 2004, Xu 2011, Yu 2013, Chang 2016, Dong 2016). Several other variants involving this codon have been identified in individuals with Noonan syndrome and/or hematological malignancies. In summary, this variant meets criteria to be classified as pathogenic for JMML. -

RASopathy Pathogenic:1Uncertain:1
Feb 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 76 of the PTPN11 protein (p.Glu76Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (JMML) (PMID: 12717436, 14644997, 14982869). ClinVar contains an entry for this variant (Variation ID: 13336). 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: 14974085, 19509418). This variant disrupts the p.Glu76 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 12634870, 16830086, 18678287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

-
Baylor Genetics
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

Variant classified using ACMG guidelines -

Noonan syndrome 1 Pathogenic:1
Dec 18, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

PTPN11-related disorder Pathogenic:1
-
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has not been previously reported as a germline variant to our knowledge; however, it has been observed as a somatic variant in individuals with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (PMID:14644997, 14982869, 12717436). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with PTPN11 - related disorders. Different amino acid changes at the same residue (p.Glu76Asp, p.Glu76Gln, p.Glu76Gly, p.Glu76Val) have been previously reported in individuals with Noonan syndrome and/or hematological malignancies (PMID: 16830086, 11704759, 18678287, 12634870). Functional studies showed that the c.226G>A (p.Glu76Lys) variant has a gain-of-function effect on the PTPN11 protein (PMID: 14974085, 19509418, 27783593). It is absent from the gnomAD population database and thus is presumed to be rare. The c.226G>A (p.Glu76Lys) variant 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.226G>A (p.Glu76Lys) variant is classified as Pathogenic. -

Noonan syndrome Pathogenic:1
May 10, 2013
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Malignant neoplastic disease Uncertain:1
-
Investigational Cancer Therapeutics, MD Anderson Cancer Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

- -

Neoplasm Other:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:-
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
.;.;.;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
M;M;.;M
PhyloP100
10
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-3.5
D;D;.;.
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0070
D;D;.;.
Sift4G
Uncertain
0.012
D;D;.;D
Polyphen
0.99
D;D;.;.
Vest4
0.94
MutPred
0.76
Gain of methylation at E76 (P = 0.0223);Gain of methylation at E76 (P = 0.0223);Gain of methylation at E76 (P = 0.0223);Gain of methylation at E76 (P = 0.0223);
MVP
0.99
MPC
2.0
ClinPred
0.98
D
GERP RS
5.9
Varity_R
0.98
gMVP
0.88
Mutation Taster
=1/99
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918464; hg19: chr12-112888210; COSMIC: COSV61004889; COSMIC: COSV61004889; API