12-112450352-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.172A>G(p.Asn58Asp) 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N58H) has been classified 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:23

Conservation

PhyloP100: 9.31

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 19 ACMG points.

PM1

In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) 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 chr12-112450352-A-C 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, 0.971

PP5

Variant 12-112450352-A-G is Pathogenic according to our data. Variant chr12-112450352-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450352-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112450352-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5 link	c.172A>G	p.Asn58Asp	missense_variant	Exon 3 of 16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.172A>G	p.Asn58Asp	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 link	c.172A>G	p.Asn58Asp	missense_variant	Exon 3 of 15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

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:7

Apr 26, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PS2; PS4M; PM1; PP2; PP3; PP5 -

Oct 10, 2024

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_v1.3.5, 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). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 103 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Asn58His) has been well reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic by more than ten accredited laboratories in ClinVar. (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 -

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.172A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid asparagine at position 58 in the protein to aspartic acid. This variant has been identified as a de novo variant in this fetus (PS2). The variant has been reported in 8 probands with a clinical presentation of Noonan Syndrome (e.g. PMID: 15001945; PMID: 16804314) (PS4). This variant is absent from population databases (PM2). This variant is a missense change at an amino acid residue where multiple different missense changes have been seen before in association with disease (e.g. PMID: 12634870) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397507505) and in the HGMD database: CM044250. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40487). -

Jul 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. he variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040487). Different missense changes at the same codon (p.Asn58His, p.Asn58Lys, p.Asn58Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040486, VCV000040488, VCV000040489, VCV000181494). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 06, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:5

Feb 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19077116, 16804314, 32164556, 32059087, 19125092, 24803665, 15956085, 26918529, 15001945, 20030748, 18678287, 30693642, 30556322, 33144682, 33726816, 11992261, 16053901, 29493581, 9491886) -

May 20, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11: PM1, PM2, PM5, PM6, PS4:Moderate, PP3 -

Aug 12, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.172A>G, in exon 3 that results in an amino acid change, p.Asn58Asp. This sequence change is not present in large population databases such as ExAC and gnomAD. The p.Asn58Asp change affects a moderately conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn58Asp substitution. This variant has been reported in several individuals with a clinical diagnosis of Noonan syndrome, occurring de novo in at least 3 of these individuals (PMID:15001945, PMID:15956085, PMID:18678287, PMID:19077116, PMID:20030748, PMID:21590266). Furthermore, missense variants affecting the same amino acid residue (p.Asn58Lys and p.Asn58His) and nearby residues have also been reported in association with Noonan syndrome supporting the functional importance of protein domain (PMID: 12634870, PMID: 16263833). This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively. -

Mar 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.172A>G; p.Asn58Asp variant (rs397507505, ClinVar ID: 40487) has been reported in multiple patients diagnosed with Noonan syndrome, including individuals where it was a de-novo alteration (Zenker 2004, Ferreira 2005, Ferrero 2008, Pierpont 2009, Tumurkhuu 2010, Papadopoulou 2012). The variant is located in the N-SH2 domain of PTPN11 (Hof 1998), and other variants at this residue have been implicated in Noonan syndrome (Tartaglia 2006). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism and computational analyses predict that this variant is deleterious (REVEL: 0.757). Based on available information, the p.Asn58Asp variant is considered to be pathogenic. References: Ferreira LV et al. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5156-60. PMID: 15956085. Ferrero GB et al. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. 2008 Nov-Dec;51(6):566-72. PMID: 18678287. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886. Papadopoulou A et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012 Jan;171(1):51-8. PMID: 21590266. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. PMID: 19077116. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218. Tumurkhuu M et al. Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway. Pediatr Int. 2010 Aug;52(4):557-62. PMID: 20030748. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 Mar;144(3):368-74. PMID: 15001945. -

PTPN11-related disorder

Pathogenic:2

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with Noonan syndrome, including several individuals in whom the variant was reported as a de novo change (PMID: 19125092, 21590266, 15001945, 16804314, 15956085, 18678287, 19077116, 20030748, 32164556). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with Noonan syndrome (PMID: 11992261). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.172A>G (p.Asn58Asp) variant is classified as Pathogenic. -

May 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.172A>G variant is predicted to result in the amino acid substitution p.Asn58Asp. This variant has been reported in multiple individuals with Noonan syndrome including at least one report of it occurring de novo (see for example - Zenker et al. 2004. PubMed ID: 15001945; Kitsiou-Tzeli et al. 2006. PubMed ID: 16804314; Hakami et al. 2016. PubMed ID: 26918529). Additionally, different missense variants affecting this amino acid (p.Asn58His, p.Asn58Tyr, p.Asn58Ser, p.Asn58Lys) have been reported as pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

RASopathy

Pathogenic:2

Oct 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PTPN11 c.172A>G (p.Asn58Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant has been reported in multiple patients with Noonan syndrome and is absent in 277532 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 58 of the PTPN11 protein (p.Asn58Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features or diagnoses of Noonan syndrome (PMID: 15001945, 15956085, 16804314, 19077116, 19125092, 21590266). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40487). 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. -

LEOPARD syndrome 1

Pathogenic:1

Jul 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metachondromatosis

Pathogenic:1

Jul 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Dec 01, 2023

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Noonan syndrome

Pathogenic:1

Mar 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asn58Asp variant in PTPN11 has previously been identified in >10 individuals with clinical features of Noonan syndrome, including at least 3 individuals whe re the variant was reported to have occurred de novo (Zenker 2004, Ferrero 2008, Ferreira 2005, Kitsiou-Tzeli 2006, Pierpont 2009, Tumurkhuu 2010, LMM unpublish ed data). This variant was not identified in large population studies. In summar y, this variant meets our criteria to be classified as pathogenic (http://pcpgm. partners.org/LMM). -

Cardiovascular phenotype

Pathogenic:1

Dec 03, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172A>G (p.N58D) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from an A to G substitution at nucleotide position 172, causing the asparagine (N) at amino acid position 58 to be replaced by an aspartic acid (D). for PTPN11-related RASopathy; however, it is unlikely to be causative of metachondromatosis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was determined to be de novo in at least one individual with features consistent with PTPN11-related RASopathy (Ferreira, 2005; Kitsiou-Tzeli, 2006). This amino acid position is highly conserved in available vertebrate species. This variant is located in a mutation hotspot in the N-terminal Src homology 2 domain and is indicated to be structurally deleterious (Ambry internal data; Russo, 1998). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11 NM_002834.4 exon 3 p.Asn58Asp (c.172A>G): This variant has been reported in the literature in at least 6 individuals with Noonan syndrome, occuring de novo in at least 3 of these individuals (Zenker 2004 PMID:15001945, Ferreira 2005 PMID:15956085, Ferrero 2008 PMID:18678287, Pierpont 2009 PMID:19077116, Tumurkhuu 2010 PMID:20030748, Papadopolou 2012 PMID:21590266). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40487). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, this variant occurs within the N-SH2 domain, a critical region for the function of this gene, and increases the likelihood that this variant is damaging (Tartaglia 2002 PMID: 11992261, Strullu 2014 PMID:25097206). Furthermore, two other variants at this position (p.Asn58His and p.Asn58Lys) have also been reported in association with disease, supporting that this region has significance. In summary, this variant is classified as pathogenic -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Feb 03, 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

0.99

CardioboostCm

Uncertain

0.73

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

.;.;.;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.3

L;L;.;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.5

D;D;.;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.018

D;D;.;.

Sift4G

Uncertain

0.024

D;D;.;D

Polyphen

1.0

D;D;.;.

Vest4

0.92

MutPred

0.93

Loss of methylation at K55 (P = 0.1138);Loss of methylation at K55 (P = 0.1138);Loss of methylation at K55 (P = 0.1138);Loss of methylation at K55 (P = 0.1138);

MVP

0.90

MPC

2.0

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.75

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