12-112450362-A-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.182A>G(p.Asp61Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,050 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. D61H) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PTPN11
NM_002834.5 missense
NM_002834.5 missense
Scores
10
8
2
Clinical Significance
Conservation
PhyloP100: 9.31
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 domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) 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-C is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ: 3.1293 (greater than the threshold 3.09). Trascript score misZ: 4.9438 (greater than threshold 3.09). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. GenCC has associacion of the gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 12-112450362-A-G is Pathogenic according to our data. Variant chr12-112450362-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450362-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112450362-A-G is described in Lovd as [Pathogenic]. Variant chr12-112450362-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461050Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726854
GnomAD4 exome
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2
AN:
1461050
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Cov.:
31
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AC XY:
1
AN XY:
726854
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:29
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Noonan syndrome 1 Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Apr 30, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 20, 2022 | The PTPN11 c.182A>G (p.Asp61Gly) missense variant results in the substitution of asparagine at amino acid position 61 with glycine. This variant is one of the most commonvPTPN11 variants reported in association with Noonan syndrome. Across a selection of the available literature, the c.182A>G variant has been reported in at least 28 individuals with Noonan syndrome, at least six of whom also showed features of juvenile myelomonocytic leukemia or myeloproliferative disorder (PMID: 11992261; PMID: 15928039; PMID: 25097206; PMID: 26084119). The c.182A>G variant has also been shown to occur de novo in at least two additional affected individuals (PMID: 23321623; PMID: 26242988). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Structural modeling has shown that asparagine 61 is located at the N-SH2/PTP interaction surface, which is a mutational hotspot (PMID: 11992261), and functional assays have demonstrated that the variant enhances basal protein activity (gain of function) (PMID: 15987685). A heterozygous knock-in mouse model with the p.Asp61Gly amino acid change exhibits decreased viability and recapitulates clinical features of Noonan syndrome, including short stature, craniofacial anomalies, and myeloproliferative disease (PMID: 15273746). This variant was also identified in a de novo state. Based on the available evidence, the c.182A>G (p.Asp61Gly) variant is classified as pathogenic for Noonan syndrome. - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Jul 08, 2022 | ACMG Criteria: PS2, PS3, PM1, PM2_P, PM5, PP2, PP3, PP5; Variant was found heterozygously in de novo-status by prenatal trio exome sequence analysis. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 28, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics, Centre for Human Genetics | - | - - |
| Likely pathogenic, no assertion criteria provided | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | May 31, 2019 | - - |
not provided Pathogenic:8
| 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 | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| 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 | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | PTPN11: PS2, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2022 | A published mouse model demonstrates that homozygous expression of the p(D61G) mutant is embryonic lethal, whereas heterozygotes have decreased viability and the surviving mice had features of Noonan syndrome and myeloproliferative disease, mimicking the human phenotype (Araki et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); Published functional studies demonstrate that p.(D61G) leads to enhanced basal activity of the protein compared to wild type (gain of function effect) (Keilhack et al., 2005); This variant is associated with the following publications: (PMID: 30355600, 30029678, 32164556, 19835954, 20651068, 24628801, 16377799, 19008228, 24718990, 27521173, 26242988, 24803665, 25383899, 22371576, 28328117, 28346493, 27924582, 11704759, 28366775, 28378436, 29659837, 30417923, 26918529, 30050098, 29907801, 31219622, 29146900, 31617209, 31324109, 33971972, 32981126, 32499374, 34006472, 11992261, 9491886, 16053901, 29493581, 15273746, 15987685) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 01, 2013 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
RASopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 08, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 61 of the PTPN11 protein (p.Asp61Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and is one of the most commonly reported variants in this condition. It has also been observed in an individual with juvenile myelomonocytic leukemia. (PMID: 11704759, 11992261, 12634870, 15928039, 16358218, 17020470, 22420426, 23321623, 26084119, 26242988). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13330). 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: 15273746, 15987685, 16377799, 19008228). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 29, 2020 | Variant summary: PTPN11 c.182A>G (p.Asp61Gly) 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 251804 control chromosomes. c.182A>G has been well reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (example, Tartaglia_2001, Musante_2003, Bertola_2006, Kosaki_2002, Ferreira_2008, Strullu_2014). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function leading to activation of the Ras-ErK signaling pathway (example, Hu_2015). Five 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. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
LEOPARD syndrome 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 28, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. - |
Short stature;C4049796:Abnormal cardiovascular system morphology Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Metachondromatosis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 28, 2022 | - - |
Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 14, 2015 | The p.Asp61Gly variant in PTPN11 has been previously reported in >30 individuals with Noonan syndrome with or without juvenile myelomonocytic leukemia (JMML) in cluding at least 5 de novo occurrences (Tartagila 2001, Kosaki 2002, Yoshida 200 4, Kratz 2005, Bertola 2006, Chan 2006, Shaw 2007, Noordam 2005, Strullu 2014, B ouchikhi 2015, LMM data). It was also identified as a somatic variant in 1 child with acute lymphoblastic leukemia (ALL) and 2 children with JMML (Yamamoto 2006 , Stullu 2014). It has not been identified in large population studies. Both in vivo animal models and in vitro studies provide evidence that this variant impac ts protein function (Araki 2004, Kontaridis 2006, Uhlen 2006, Eminaga 2008, Wang 2009, Xu 2010, De Rocca 2012, Bonetti 2014, Lee 2014). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome and JMML in an autosomal dominant manner. - |
PTPN11-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 18, 2024 | The PTPN11 c.182A>G variant is predicted to result in the amino acid substitution p.Asp61Gly. This variant has been repeatedly reported in individuals with Noonan syndrome and is one of the most common pathogenic variants in PTPN11 (see for example Tartaglia et al 2001. PubMed ID: 11704759). In at least two individuals it was reported as a de novo event (Croonen et al. 2013. PubMed ID: 23321623; Joyce et al. 2015. PubMed ID: 26242988). In vitro functional studies and knock-in mouse models are consistent with this variant disrupting normal protein function (Araki et al. 2004. PubMed ID: 15273746; Keilhack et al. 2005. PubMed ID: 15987685; Serra-Nédélec. 2012. PubMed ID: 22371576). This variant has been interpreted as pathogenic by multiple labs in ClinVar. Additionally, different amino acid substitutions (p.Asp61Asn, p.Asp61His, p.Asp61Ala, p.Asp61Val) affecting the same amino acid have been reported as pathogenic (ClinVar IDs: 40495, 40494, 179221, 40496). This variant is interpreted as pathogenic. - |
Noonan syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2011 | - - |
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 | Oct 22, 2021 | - - |
Non-immune hydrops fetalis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Aug 13, 2020 | - - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 17, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
N;N;.;N
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.
Sift4G
Uncertain
T;D;.;D
Polyphen
P;P;.;.
Vest4
MutPred
Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);Loss of solvent accessibility (P = 0.0674);
MVP
MPC
2.2
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at