chr12-112450362-A-G

Variant names:

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:29

Conservation

PhyloP100: 9.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a strand (size 2) in uniprot entity PTN11_HUMAN there are 16 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 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 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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.182A>G	p.Asp61Gly	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
PTPN11	ENST00000351677.7 link	c.182A>G	p.Asp61Gly	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.182A>G	p.Asp61Gly	missense_variant	Exon 3 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461050

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726854

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Feb 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.182A>G; p.Asp61Gly variant (rs121918461), is reported in the literature in numerous individuals affected with Noonan syndrome with or without juvenile myelomonocytic leukemia or other myeloproliferative disorders, including at least one instance of de novo inheritance (Araki 2004, Athota 2020, Bonetti 2014, Brannon 2014, Keilhack 2005, Kontaridis 2006, Kratz 2005, Musante 2003, Strullu 2014, Tartaglia 2002, Tartaglia 2001, Xu 2010, Yoshida 2004). This variant is also reported in ClinVar (Variation ID: 13330) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. In vitro functional analyses demonstrate that this variant causes increased basal activity of the PTPN11 protein and mouse and zebrafish models expressing this variant have features that are consistent with Noonan syndrome (Araki 2004, Bonetti 2014, Keilhack 2005, Kontaridis 2006, Xu 2010). Computational analyses predict that this variant is deleterious (REVEL: 0.92). Based on available information, this variant is considered to be pathogenic. References: Araki T et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med. 2004 Aug. PMID: 15273746. Athota JP et al. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med Genet. 2020 Mar 12. PMID: 32164556. Bonetti M et al. Noonan and LEOPARD syndrome Shp2 variants induce heart displacement defects in zebrafish. Development. 2014 May. PMID: 24718990. Brannon AR et al. Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol. 2014 Aug 28. PMID: 25164765. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2. PMID: 15987685. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10. PMID: 16377799. Kratz CP et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005 Sep 15. PMID: 15928039. Musante L et al. Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet. 2003 Feb. PMID: 12634870. Strullu M et al. Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet. 2014 Oct. PMID: 25097206. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun. PMID: 11992261. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature genetics. 2001 Dec. PMID: 11704759. Xu D et al. A germline gain-of-function mutation in Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells. Blood. 2010 Nov 4. PMID: 20651068. Yoshida R et al. Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. J Clin Endocrinol Metab. 2004 Jul. PMID: 15240615 -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2015

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: no assertion criteria provided

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

- -

Mar 18, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11: PS2, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

Noonan syndrome 1

Pathogenic:8

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Apr 30, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 20, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 28, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 08, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Molecular Genetics, Centre for Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Pathogenic:3

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 29, 2020

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.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. -

Oct 08, 2024

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 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. -

LEOPARD syndrome 1

Pathogenic:2

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. -

Jun 28, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Short stature;C4049796:Abnormal cardiovascular system morphology

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metachondromatosis

Pathogenic:1

Jun 28, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia

Pathogenic:1

Jul 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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

Pathogenic:1

Oct 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Non-immune hydrops fetalis

Pathogenic:1

Aug 13, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jul 17, 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

1.0

CardioboostCm

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;.;.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

0.59

N;N;.;N

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.9

D;D;.;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;D;.;.

Sift4G

Uncertain

0.057

T;D;.;D

Polyphen

0.82

P;P;.;.

Vest4

0.98

MutPred

0.91

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

1.0

MPC

2.2

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.75

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over