rs397507545

Positions:

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 same amino acid change has been previously reported as Pathogenicin 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:

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 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). GenCC has associacion of 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, 0.988

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/exons	MANE	Protein
PTPN11	NM_002834.5 linkuse as main transcript	c.1507G>A	p.Gly503Arg	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2 linkuse as main transcript	c.1519G>A	p.Gly507Arg	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1 linkuse as main transcript	c.1504G>A	p.Gly502Arg	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3 linkuse as main transcript	c.1516G>A	p.Gly506Arg	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.1507G>A	p.Gly503Arg	missense_variant	13/16	1	NM_002834.5	ENSP00000340944	A1	Q06124-2

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

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Dec 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 15, 2021	ACMG classification criteria: PS1 strong, PS4 strong, PM2 moderate, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Nov 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	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. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

LEOPARD syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 22, 2022

- -

Metachondromatosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 22, 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

Mar 23, 2018

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2023

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

Pathogenic, no assertion criteria provided

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 27, 2010

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 21, 2021

- -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

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). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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;.

MutationTaster

Benign

1.0

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