rs397507545

Variant names:

Your query was ambiguous. Multiple possible variants found:

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>A(p.Gly503Arg) 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. 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23

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-A is Pathogenic according to our data. Variant chr12-112489083-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 40559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489083-G-A is described in Lovd as [Pathogenic]. Variant chr12-112489083-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:10

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.1507G>A (p.Gly503Arg) variant in the PTPN11 gene has been observed in multiple individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (Cammarata-Scalisi, Francisco et al., 2012). It has also been observed to segregate with disease in related individuals. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic (multiple submissions). The amino acid Glycine at position 503 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT.The amino acid change p.Gly503Arg in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Jul 15, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS1 strong, PS4 strong, PM2 moderate, PP2 supporting, PP3 supporting -

Dec 05, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040558,VCV000040559,VCV000571101). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040561, PMID:16358218). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992>=0.6, 3CNET: 0.994>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 23, 2022

Eurofins-Biomnis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2023

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) is associated with loss of function variants, whereas Noonan syndrome (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). Variants that cause Noonan syndrome with multiple lentigines have a loss of function effect at the protein level but result in gain of function properties (PMID: 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMID: 32164556). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Noonan syndrome in ClinVar and the literature (ClinVar, PMID: 32164556). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:4

Mar 08, 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: 18678287, 28628100, 15928039, 23513489, 24803665, 25533962, 27288520, 25862627, 28135719, 16358218, 28191890, 18470943, 23756559, 22465605, 30202406, 30050098, 29907801, 32164556, 33673806, 29493581, 31785789) -

Nov 16, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metachondromatosis

Pathogenic:1

Aug 22, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LEOPARD syndrome 1

Pathogenic:1

Aug 22, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 (c.1507G>A) variant in PTPN11 has been reported as a somatic cha nge in at least 1 individual with a hematologic malignancy and as a germline cha nge in >10 individuals with clinical features of Noonan syndrome, including at l east 1 apparently de novo occurrence (Tartaglia 2006, Ferrero 2008, Cammarata-Sc alisi 2012, LMM data). This variant has also been reported in ClinVar (Variation ID 40559) and was absent from large population studies. In addition, the p.Gly5 03Arg variant due to a different nucleotide substitution (c.1507G>C) has also be en reported in individuals with Noonan syndrome, Noonan syndrome with juvenile m yelomonocytic leukemia (JMML), JMML, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Tartaglia 2006, Lo 2008). Three other variants involving this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as pathogenic. Computational prediction tools and conservation analysis suggest that the p.Gly5 03Arg variant may impact the protein. In summary, this variant meets criteria 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

Nov 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.1507G>A variant is predicted to result in the amino acid substitution p.Gly503Arg. This variant has been reported as a recurrent variant to be causative for Noonan syndrome and neurodevelopment disorders (see for example - Tartaglia et al. 2006. PubMed ID: 16358218; Cammarata-Scalisi et al. 2012. PubMed ID: 23513489; Geisheker et al. 2017. PubMed ID: 28628100, reported as de novo in Table S4; Leach et al. 2019. PubMed ID: 29907801, Table 2). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, an alternate nucleotide substitution (c.1507G>C) resulting in the same missense variant (p.Gly503Arg) and alternate missense variants (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) affecting this amino acid have been reported as pathogenic (Human Gene Mutation Database). This variant is interpreted as pathogenic. -

Noonan syndrome

Pathogenic:1

Aug 27, 2010

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Nov 21, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G503R pathogenic mutation (also known as c.1507G>A), located in coding exon 13 of the PTPN11 gene, results from a G to A substitution at nucleotide position 1507. The glycine at codon 503 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and c.1507G>T which leads to the same amino acid change, have been reported in a number of individuals with Noonan syndrome and related malignancies (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Lo FS et al. Int. J. Hematol., 2008 Oct;88:287-90; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Holmfeldt L et al. Nat. Genet., 2013 Mar;45:242-52; Mathur D et al. Fetal Pediatr Pathol, 2014 Aug;33:253-7). Based on internal structural analysis, this variant is predicted to be structurally destabilizing (Hof P et al. Cell. 1998 Feb;92(4):441-50; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Pathogenic:1

Dec 24, 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 not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome or Noonan syndrome with multiple lentigines (PMID: 15001945, 16358218, 18678287, 18758896, 22465605, 23513489). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40559). 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. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jun 21, 2021

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

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