chr12-112489068-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.1492C>T(p.Arg498Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,956 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. R498L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 2.30

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 17 ACMG points.

PM1

In a helix (size 8) in uniprot entity PTN11_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002834.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112489069-G-T 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 12-112489068-C-T is Pathogenic according to our data. Variant chr12-112489068-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489068-C-T is described in Lovd as [Pathogenic]. Variant chr12-112489068-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.1492C>T	p.Arg498Trp	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.1492C>T	p.Arg498Trp	missense_variant	Exon 13 of 16	1	NM_002834.5	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1 link	c.1504C>T	p.Arg502Trp	missense_variant	Exon 13 of 15	5		ENSP00000489597.1	Q06124-1
PTPN11	ENST00000635652.1 link	c.505C>T	p.Arg169Trp	missense_variant	Exon 5 of 5	3		ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251490

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

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:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727194

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:5

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 21, 2023

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 of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187; ClinGen expert panel). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Noonan syndrome is known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 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). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in individuals with LEOPARD syndrome or Noonan syndrome (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Jan 11, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM5, PS2, PS3_moderate, PS4 -

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.1492C>T; p.Arg498Trp variant (rs397507541) is reported in the literature in multiple individuals diagnosed with Noonan syndrome with multiple lentigines (also known as LEOPARD syndrome 1) or Noonan syndrome (Chen 2019, Giugliano 2019, Hakami 2016, Kauffman 2021, Li 2019, Marinakis 2021, Sarkozy 2004). This variant is also reported in ClinVar (Variation ID: 40553). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, another amino acid substitution at this codon (c.1493G>T; p.Arg498Leu) has been reported in individuals with Noonan syndrome with multiple lentigines or Noonan syndrome, and is considered pathogenic (Hung 2007, Limongelli 2008, Sarkozy 2004). In vitro functional analyses of the variant protein demonstrate loss of phosphatase activity, consistent with established disease mechanisms of Noonan syndrome with multiple lentigines (Gelb 2007, Rauen 2013). Computational analyses predict that this variant is deleterious (REVEL: 0.849). Based on available information, this variant is considered to be pathogenic. References: Chen H et al. Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort. Orphanet J Rare Dis. 2019 Feb 7;14(1):29. PMID: 30732632. Edwards JJ et al. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. PMID: 24891296. Giugliano T et al. Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. Genes (Basel). 2019 Jul 31;10(8):580. PMID: 31370276. Gelb BD and Tartaglia M. Noonan Syndrome with Multiple Lentigines. 2007 Nov 30 [updated 2022 Jun 30]. GeneReviews® [Internet]. 1993–2023. PMID: 20301557. 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. Hung CS et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. PMID: 17339163. Kauffman H et al. Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. Pediatr Res. 2021 Aug;90(2):444-451. PMID: 33318624. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Limongelli G et al. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am J Med Genet A. 2008 Mar 1;146A(5):620-8. PMID: 18241070. Marinakis NM et al. Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. Am J Med Genet A. 2021 Aug;185(8):2561-2571. PMID: 34008892. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-69. PMID: 23875798. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. PMID: 15121796. -

Jan 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the resulting protein is catalytically impaired, has significantly reduced basal activity, and has a reduced response to stimulation with phosphotyrosol (Edwards et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 29693080, 17056636, 30417923, 30732632, 32059087, 15121796, 24891296, 23239957, 16369799, 15928039, 20301557, 27562378, 24803665, 29356064, 29988639, 21533187, 9222968, 27521173, 11704759, 12960218, 19206169, 21500339, 24935154, 17875892, 18241070, 17339163, 26918529, 31219622, 22190897, 31370276, 33318624, 34008892, 32746448, 33726816, 29493581, 27535533) -

Aug 12, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

LEOPARD syndrome 1

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040553, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040554, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.849, 3CNET: 0.858, PP3_P). A missense variant is a common mechanism associated with LEOPARD syndrome 1 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 27, 2019

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. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -

Feb 06, 2024

Baylor Genetics

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:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2+PP3+PM6+PS4+PM1 -

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:2

Apr 11, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R498W pathogenic mutation (also known as c.1492C>T), located in coding exon 13 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1492. The arginine at codon 498 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in multiple unrelated individuals reported to have Noonan syndrome (NS) or Noonan syndrome with multiple lentigines (NSML) or features consistent with NS/NSML, including reported de novo occurrences, and has been reported to segregate with disease features in families (Sarkozy A et al. J Med Genet, 2004 May;41:e68; Kratz CP et al. Blood, 2005 Sep;106:2183-5; Lepri FR et al. BMC Med Genet, 2014 Jan;15:14; Edwards JJ et al. Am J Med Genet A, 2014 Sep;164A:2351-5; Ramos-Geldres TT et al. Actas Dermosifiliogr, 2015 May;106:e19-22; Bademci G et al. Sci Rep, 2016 Aug;6:31622; Hakami F et al. Prenat Diagn, 2016 May;36:418-23; McDonald BS et al. Clin Exp Dermatol, 2018 Apr;43:357-359; Bulteel C et al. JAAD Case Rep, 2018 May;4:390-391; Giugliano T et al. Genes (Basel), 2019 Jul;10; Li X et al. Clin Genet, 2019 Oct;96:290-299; Bessis D et al. Br J Dermatol, 2019 Jun;180:1438-1448; Kauffman H et al. Pediatr Res, 2021 Aug;90:444-451; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is unclear. -

Institute of Human Genetics, Medical University Innsbruck

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy

Pathogenic:2

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 498 of the PTPN11 protein (p.Arg498Trp). This variant is present in population databases (rs397507541, gnomAD 0.0009%). This missense change has been observed in individual(s) with Noonan syndrome with multiple lentigines and PTPN11-related conditions (PMID: 15121796, 22190897, 24891296, 27562378; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40553). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 24891296). This variant disrupts the p.Arg498 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15121796, 17339163, 17875892, 18241070, 24935154). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Metachondromatosis

Pathogenic:1

Feb 06, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTPN11-related disorder

Pathogenic:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.1492C>T variant is predicted to result in the amino acid substitution p.Arg498Trp. This variant has been reported to be causative for Noonan spectrum disorders (see for example, Sarkozy et al. 2004. PubMed ID: 15121796). Functional studies demonstrate this variant results in reduced phosphatase activity (Edwards et al. 2014. PubMed ID: 24891296). This variant is also interpreted by multiple clinical labs as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/40553/). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines

Pathogenic:1

Oct 06, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg498Trp variant in PTPN11 has been identified in at least 10 individuals with clinical features of LEOPARD syndrome (LS) or Noonan syndrome with or with out myeloproliferative disorder, and segregated with clinical features in famili es (NS/MPD; Kratz 2005, Kratz 2006, Sarkozy 2004, LMM data). It has not been ide ntified in large population studies. Missense variants in PTPN11 are strongly as sociated with Noonan spectrum disorders, and another variant (p.Arg498Leu) affec ting the same amino acid residue is known pathogenic. In summary, this variant m eets criteria to be classified as pathogenic for autosomal dominant Noonan spect rum disorders. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jun 01, 2020

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

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

.;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

.;H;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.6

D;.;.

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.98

MutPred

0.98

Loss of disorder (P = 0.0078);.;.;

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.99

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