12-112489083-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.1507G>C(p.Gly503Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G503E) 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:19

Conservation

PhyloP100: 9.60

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:

LOC124903024 (HGNC:):

LOC124903024 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 23 ACMG points.

PS1

Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) 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 chr12-112489084-G-A 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, 0.988

PP5

Variant 12-112489083-G-C is Pathogenic according to our data. Variant chr12-112489083-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489083-G-C is described in Lovd as [Pathogenic]. Variant chr12-112489083-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.1507G>C	p.Gly503Arg	missense_variant	Exon 13 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTPN11	ENST00000351677.7 link	c.1507G>C	p.Gly503Arg	missense_variant	Exon 13 of 16	1	NM_002834.5	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1 link	c.1519G>C	p.Gly507Arg	missense_variant	Exon 13 of 15	5		ENSP00000489597.1	Q06124-1
PTPN11	ENST00000635652.1 link	c.520G>C	p.Gly174Arg	missense_variant	Exon 5 of 5	3		ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251492

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

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:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:6

Jul 09, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 26, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS1,PS4,PM6,PP3,PP4,PP5 -

Feb 26, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PM1, PM2, PM5, PP2, PP3, PP5 -

Aug 29, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 28117207). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000992499 /PMID: 28117207 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 26, 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

- -

not provided

Pathogenic:6

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.1507G>C; p.Gly503Arg variant (rs397507545) is reported in the literature in multiple individuals affected with Noonan syndrome and has been reported de novo in several (Chaves Rabelo 2022, Chinton 2019, Faggetter 2023, Hakami 2016, Matalon 2021, Mathus 2014, Sarkozy 2003). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.992). Based on available information, this variant is considered to be pathogenic. References: Chaves Rabelo N et al. RASopathy Cohort of Patients Enrolled in a Brazilian Reference Center for Rare Diseases: A Novel Familial LZTR1 Variant and Recurrent Mutations. Appl Clin Genet. 2022 Oct 21;15:153-170. PMID: 36304179. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. PMID: 31560489. Faggetter S et al. Hereditary spherocytosis associated with Noonan syndrome mimicking a dyserythropoietic anaemia. Pediatr Blood Cancer. 2023 Apr;70(4):e30121. PMID: 36579772. Hakami F et al. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn. 2016 May;36(5):418-23. PMID: 26918529. Matalon DR et al. Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies. Am J Med Genet A. 2021 May;185(5):1486-1493. PMID: 33683002. Mathur D et al. Twin infant with lymphatic dysplasia diagnosed with Noonan syndrome by molecular genetic testing. Fetal Pediatr Pathol. 2014 Aug;33(4):253-7. PMID: 24754368. Sarkozy A et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003 Sep;40(9):704-8. PMID: 12960218. -

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a germline variant in patients with features of a Noonan spectrum disorder and myeloproliferative disease or leukemia (including JMML and AML), and in one patient with features of a Noonan spectrum disorder and Hodgkin's lymphoma (Tartgalia et al., 2003; Lo et al., 2008; Bluteau et al., 2018); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19737548, 23334668, 16358218, 24754368, 29703613, 30355677, 30670449, 29037749, 26918529, 18758896, 30417923, 15001945, 22681964, 19077116, 27592337, 15928039, 29146883, 30050098, 29907801, 31560489, 33144682, 29493581, 33683002, 33318624, 34008892, 12960218, 12717436) -

Feb 25, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1, PS4, PM5, PM6, PP2, PP3 -

Oct 05, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Pathogenic:2

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 503 of the PTPN11 protein (p.Gly503Arg). This variant is present in population databases (rs397507545, gnomAD 0.004%). This missense change has been observed in individuals with Noonan syndrome or Leopard syndrome (PMID: 12717436, 12960218, 16358218, 18758896, 19077116, 19737548, 24754368). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40558). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 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.1507G>C (p.Gly503Arg) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 252092 control chromosomes. c.1507G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions, including a father and daughter showing co-segregation with disease (e.g. Zenker_2004, Tartaglia_2006, Lo_2008, Pierpont_2009, Mathur_2014, Bessis_2019, Chinton_2019). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia

Pathogenic:1

Mar 23, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly503Arg (due to c.1507G>C or c.1507G>A) variant has previously been repo rted >10 individuals with the clinical features of Noonan syndrome, including at least 2 de novo occurrences (Tartaglia 2003, Sarkozy 2003, Zenker 2004, Kratz 2 005, Lo 2008, Ezquieta 2012, LMM data). This variant has also been reported in i ndividuals with Noonan syndrome and juvenile myelomonocytic leukemia (JMML), JMM L, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Lo 2008). It ha s not been identified in large population studies. Three other variants involvin g this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as patho genic. Computational prediction tools and conservation analysis suggest that the p.Gly503Arg variant may impact the protein. In summary, this variant meets crit eria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4; PM1; PM2; PM6; PP3. -

PTPN11-related disorder

Pathogenic:1

Apr 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.1507G>C variant is predicted to result in the amino acid substitution p.Gly503Arg. This variant is located in a mutational hotspot region of the PTPN11 gene. It has been repeatedly reported to be causative for Noonan syndrome (Sarkozy et al. 2003. PubMed ID: 12960218; Holmfeldt et al. 2013. PubMed ID: 23334668; Chinton et al. 2019. PubMed ID: 31560489). Additionally, a different variant, 1507G>A, that results in the same amino acid change has been reported as causative for Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218). At PreventionGenetics, we previously detected the variant c.1507G>C in other affected patients. This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Neurodevelopmental disorder

Pathogenic:1

Feb 24, 2021

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Feb 05, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G503R pathogenic mutation (also known as c.1507G>C), located in coding exon 13 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1507. The glycine at codon 503 is replaced by arginine, an amino acid with dissimilar properties, and is located in the PTP domain of the PTPN11 protein. This mutation has been reported in multiple individuals with Noonan syndrome, including at least two affected parent-child pairs (Sarkozy A et al. J Med Genet, 2003 Sep;40:704-8; Lo FS et al. Int J Hematol, 2008 Oct;88:287-290; Bessis D et al. Br J Dermatol, 2019 06;180:1438-1448). The same amino acid substitution caused by a different nucleotide change (c.1507G>A) has also been reported in individuals with Noonan syndrome (Tartaglia M et al. Am J Hum Genet, 2006 Feb;78:279-90; Athota JP et al. BMC Med Genet, 2020 03;21:50). There have been reports of a few individuals with p.G503R and Noonan syndrome diagnosed with juvenile myelomonocytic leukemia (JMML) (Strullu M et al. J Med Genet, 2014 Oct;51:689-97; Kratz CP et al. Br J Cancer, 2015 Apr;112:1392-7). Based on internal structural analysis, this variant is more destabilizing than other nearby pathogenic variants (Hof P et al. Cell, 1998 Feb;92:441-50). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

.;M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.3

D;.;.

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MutPred

0.93

Gain of MoRF binding (P = 0.0178);.;.;

MVP

0.99

MPC

2.1

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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