12-112488454-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.1391G>C(p.Gly464Ala) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar 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:18O:1

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

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;

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, 0.993

PP5

Variant 12-112488454-G-C is Pathogenic according to our data. Variant chr12-112488454-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13343.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.1391G>C	p.Gly464Ala	missense_variant	Exon 12 of 16	ENST00000351677.7	NP_002825.3	Q06124-2
PTPN11	NM_001330437.2 link	c.1403G>C	p.Gly468Ala	missense_variant	Exon 12 of 16		NP_001317366.1	Q06124-1
PTPN11	NM_001374625.1 link	c.1388G>C	p.Gly463Ala	missense_variant	Exon 12 of 16		NP_001361554.1
PTPN11	XM_011538613.3 link	c.1400G>C	p.Gly467Ala	missense_variant	Exon 12 of 16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PTPN11	ENST00000351677.7 link	c.1391G>C	p.Gly464Ala	missense_variant	Exon 12 of 16	1	NM_002834.5	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1 link	c.1403G>C	p.Gly468Ala	missense_variant	Exon 12 of 15	5		ENSP00000489597.1	Q06124-1
PTPN11	ENST00000635652.1 link	c.404G>C	p.Gly135Ala	missense_variant	Exon 4 of 5	3		ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_moderate, PM1, PM2, PP2, PP3 -

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.1391G>C; p.Gly464Ala variant (rs121918469) is reported in the literature in multiple individuals and families with LEOPARD syndrome and Noonan syndrome (Baldo 2022, Nakagama 2018, Sarkozy 20004, Willig 2015). This variant is also reported in ClinVar (Variation ID: 13343). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.985). In support of these predictions, functional studies demonstrate that the variant protein has reduced catalytic activity compared to wildtype (Kontaridis 2006, Yu 2014). Based on available information, this variant is considered to be pathogenic. References: Baldo F et al. New insights on Noonan syndrome's clinical phenotype: a single center retrospective study. BMC Pediatr. 2022 Dec 24;22(1):734. PMID: 36566191. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. PMID: 16377799. Nakagama Y et al. Accelerated Cardiomyocyte Proliferation in the Heart of a Neonate With LEOPARD Syndrome-Associated Fatal Cardiomyopathy. Circ Heart Fail. 2018 Apr;11(4):e004660. PMID: 29602897. 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. Willig LK et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015 May;3(5):377-87. PMID: 25937001. Yu ZH et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014 Jul 1;53(25):4136-51. PMID: 24935154. -

Aug 26, 2014

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with Noonan syndrome with multiple lentigines (NSML and formerly called LEOPARD syndrome) and Noonan syndrome (Sarkozy et al., 2004; Ko et al., 2008; Ferrero et al., 2008); Published functional studies demonstrate expression of this variant results in reduced catalytic activity (Kontaridis et al., 2006; Yu et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17453145, 16804314, 24935154, 24718990, 16377799, 24790373, 25937001, 19020799, 15121796, 18678287, 27484170, 27666661, 16358218, 15389709, 30105547, 29263817, 30896080, 29602897, 33318624, 32746448, 29493581) -

Mar 01, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 1

Pathogenic:3

Jan 18, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM2, PM5, PP2, PP3, PP5 -

Jun 30, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PS4, PS1, PM2, PP5 -

RASopathy

Pathogenic:3

Nov 04, 2024

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.1391G>C (p.Gly464Ala) results in a non-conservative amino acid change located in the Protein tyrosine phosphatase, catalytic 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 was absent in 251186 control chromosomes. c.1391G>C has been reported in the literature in individuals affected with Noonan Syndrome (e.g. Sarkozy_2004, Willig_2015, Yoshida_2004), and also observed De Novo. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a catalytically impaired enzyme (Kontaridis_2006). The following publications have been ascertained in the context of this evaluation (PMID: 15389709, 16377799, 15121796, 25937001). ClinVar contains an entry for this variant (Variation ID: 13343). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 08, 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 alanine, which is neutral and non-polar, at codon 464 of the PTPN11 protein (p.Gly464Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LEOPARD syndrome and Noonan syndrome (PMID: 15121796, 15389709, 16358218, 18678287, 19020799, 25937001). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13343). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 24935154). For these reasons, this variant has been classified as Pathogenic. -

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

LEOPARD syndrome 1

Pathogenic:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PTPN11-related disorder

Pathogenic:1

Feb 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.1391G>C variant is predicted to result in the amino acid substitution p.Gly464Ala. This variant is well documented to be causative in patients with Noonan syndrome with or without multiple lentigines (Sarkozy et al. 2004. PubMed ID: 15121796; Willig et al. 2015. PubMed ID: 25937001; Yu et al. 2019. PubMed ID: 30896080; Yoshida et al. 2004. PubMed ID: 15389709; Tartaglia et al. 2005. PubMed ID: 16358218; Ferrero et al. 2008. PubMed ID: 18678287; Ko et al. 2008. PubMed ID: 19020799). Consistent with other PTPN11 variants that cause Noonan syndrome with multiple lentigines, functional studies found this variant results in a loss of catalytic activity that results in a dominant negative effect (Kontaridis et al. 2006. PubMed ID: 16377799; Yu et al. 2014. PubMed ID: 24935154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Noonan syndrome;C0175704:Noonan syndrome with multiple lentigines

Pathogenic:1

Mar 04, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly464Ala variant in PTPN11 has been reported in at least 2 individuals wi th clinical features of Noonan syndrome or LEOPARD syndrome (Ko 2008, Ferrero 20 08, Kitsiou-Tzeli 2006). In addition, this variant has been identified by our la boratory in 2 individuals with clinical features of a Noonan spectrum disorder. It was absent from large population studies. Furthermore, functional studies sug gest this variant has a dominant negative effect, which is an established pathog enic mechanism in LEOPARD syndrome (Kontaridis 2006, Edouard 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan or LEO PARD syndrome in an autosomal dominant manner (http://www.partners.org/personali zedmedicine/LMM). -

Cardiovascular phenotype

Pathogenic:1

Jan 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G464A pathogenic mutation (also known as c.1391G>C), located in coding exon 12 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1391. The glycine at codon 464 is replaced by alanine, an amino acid with similar properties. This mutation was identified in multiple individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome), including at least three reportedly de novo cases (Sarkozy A et al. J. Med. Genet., 2004 May;41:e68; Yoshida R et al. Am. J. Med. Genet. A, 2004 Nov;130A:432-4; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Willig LK et al. Lancet Respir Med, 2015 May;3:377-87; Noll AC et al. NPJ Genom Med, 2016 Aug;1:16026; Nakagama Y et al. Circ Heart Fail, 2018 Apr;11:e004660). In addition, functional analyses demonstrated that this mutation has a dominant negative effect and causes conformational changes in the protein structure (Kontaridis MI et al. J. Biol. Chem., 2006 Mar;281:6785-92; Yu ZH et al. Biochemistry, 2014 Jul;53:4136-51). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jun 18, 2019

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

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;D;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.1

.;H;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.8

D;.;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.95

MutPred

0.98

Loss of helix (P = 0.1299);.;.;

MVP

0.99

MPC

2.0

ClinPred

1.0

GERP RS

5.0

Varity_R

0.96

gMVP

0.98

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