12-112489080-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.1504T>G(p.Ser502Ala) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S502L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.67

Publications

30 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:

LOC124903024 (HGNC:):

LOC124903024 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr12-112489081-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 40557.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, 0.965

PP5

Variant 12-112489080-T-G is Pathogenic according to our data. Variant chr12-112489080-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40556.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.1504T>G	p.Ser502Ala	missense_variant	Exon 13 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PTPN11	ENST00000351677.7 link	c.1504T>G	p.Ser502Ala	missense_variant	Exon 13 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1 link	c.1516T>G	p.Ser506Ala	missense_variant	Exon 13 of 15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1 link	c.517T>G	p.Ser173Ala	missense_variant	Exon 5 of 5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 24, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23832011, 24803665, 15928039, 26242988, 15842656, 16358218, 31263281, 22465605, 18470943)

Feb 12, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 02, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM6_Strong, PM5, PM2, PP3

Jun 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PTPN11 c.1504T>G; p.Ser502Ala variant (rs121918458) has been reported in multiple individuals with Noonan syndrome (Joyce 2016, Kratz 2005, Sakaguchi 2013, Tartaglia 2006) or with clinical features of a neuro-cardio-facial-cutaneous syndrome (Ezquieta 2012). The variant is also reported in ClinVar (Variation ID: 40556). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1505C>T, p.Ser502Leu; c.1504T>A, p.Ser502Thr) have been reported in individuals with Noonan and LEOPARD syndromes and are considered to be causative (Tartaglia 2006). This serine residue is located in the phospho-tyrosine phosphatase domain of PTPN11 and interacts with the N-SH2 domain to mediate regulatory inhibition (Hof 1998). Computational analyses predict that this variant is deleterious (REVEL: 0.923). Based on available information, this variant is considered to be pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May. PMID: 22465605. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20. PMID: 9491886. Joyce S et al. The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. Eur J Hum Genet. 2016 May. PMID: 26242988. Kratz CP et al. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005 Sep 15. PMID: 15928039. Sakaguchi H et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature genetics. 2013 Aug. PMID: 23832011. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb. PMID: 16358218.

RASopathy

Pathogenic:2

Sep 25, 2021

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.1504T>G (p.Ser502Ala) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Other amino acid changes at this location (Ser502Thr, Ser502Ala, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome suggesting that Ser 502 is a critical amino acid essential for protein function (Tartaglia_2006). The variant was absent in 252116 control chromosomes. c.1504T>G has been reported in the literature as a de-novo germline variant in multiple individuals affected with Noonan Syndrome and related disorders as well as a somatic variant in settings of myelodysplastic related acute myeloid leukaemia (example, Kratz_2005, Tartaglia_2005, Tartaglia_2006, Kamisago_2005, Sakaguchi_2013, Ezquieta_2012, Joyce_2016). These data indicate that the variant is very likely to be associated with disease. Three 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.

Mar 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser502 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12325025, 17020470, 19020799, 32164556). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 502 of the PTPN11 protein (p.Ser502Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and/or PTPN11-related conditions (PMID: 15928039, 26242988). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40556). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function.

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia

Pathogenic:1

Jan 07, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ser502Ala variant in PTPN11 has been previously identified in 2 individuals with clinical features of Noonan syndrome, including in 1 individual where it wa s found to have occurred de novo and in 1 individual who developed juvenile myel omonocytic leukemia (JMML; Kratz 2005, Sakaguchi 2013). This variant has also be en identified in 1 individual with acute myeloid leukemia (AML; Tartaglia 2005). In addition, this variant is absent from large population studies. Three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Leu) have been associated with the clinical features of Noonan syndrome and/or LEOPARD syndrome , and have also been identified as somatic variants in individuals with hematolo gic malignancies (Tartaglia 2006, Goemans 2005, Paulsson 2007, Ko 2008, Aoki 200 8). In summary, this variant meets our criteria to be classified as pathogenic ( http://pcpgm.partners.org/LMM) based upon de novo occurrence, absence from the g eneral population, and multiple additional pathogenic variants at this position.

Cardiovascular phenotype

Pathogenic:1

Apr 14, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S502A pathogenic mutation (also known as c.1504T>G), located in coding exon 13 of the PTPN11 gene, results from a T to G substitution at nucleotide position 1504. The serine at codon 502 is replaced by alanine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Noonan syndrome; in at least one individual, it was determined to be de novo (Kratz CP et al. Blood, 2005 Sep;106:2183-5; Joyce S et al. Eur J Hum Genet, 2016 May;24:690-6; Bell JM et al. J Pediatr, 2021 Jul;234:134-141.e5; Shoji Y et al. Clin Pediatr Endocrinol, 2024 Feb;33:50-58; Ambry internal data). This variant has also been reported as somatic finding in association with hematological malignancies (Sakaguchi H et al. Nat Genet, 2013 Aug;45:937-41; Kim T et al. Leukemia, 2016 Feb;30:295-302). Other variant(s) at the same codon, p.S502T (c.1504T>A), have been identified in individual(s) with features consistent with Noonan syndrome (Athota JP et al. BMC Med Genet, 2020 Mar;21:50; Maheshwari M et al. Hum Mutat, 2002 Oct;20:298-304; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation for Noonan syndrome; however, it is unlikely to be causative of metachondromatosis.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

CardioboostCm

Uncertain

0.80

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;D;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;L;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.8

D;.;.

REVEL

Pathogenic

0.92

Sift

Benign

0.042

D;.;.

Sift4G

Benign

0.083

T;T;T

Vest4

0.73

ClinPred

0.97

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.77

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over