rs121918455

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_002834.5(PTPN11):c.923A>C(p.Asn308Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N308D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 8.89

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 19 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-112477719-A-G 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, 0.994

PP5

Variant 12-112477720-A-C is Pathogenic according to our data. Variant chr12-112477720-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40535.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.923A>C	p.Asn308Thr	missense_variant	Exon 8 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.923A>C	p.Asn308Thr	missense_variant	Exon 8 of 16	1	NM_002834.5	ENSP00000340944.3	Q06124-2
PTPN11	ENST00000635625.1 link	c.923A>C	p.Asn308Thr	missense_variant	Exon 8 of 15	5		ENSP00000489597.1	Q06124-1
PTPN11	ENST00000635652.1 link	c.-212A>C		upstream_gene_variant		3		ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with cystic hygroma and other abnormal ultrasound findings in published literature (Wilbe et al., 2017; Lee et al., 2009); 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: 18759865, 29057136, 15001945, 24803665, 28921562, 28991257, 19077116, 33318624, 32978145, 32368696, 11992261, 9491886, 16053901, 29493581) -

Apr 14, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM1, PM2_supporting, PS2, PS4 -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTPN11: PS2, PM2, PM5, PP3, PS4:Supporting -

Noonan syndrome

Pathogenic:2

Sep 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn308Thr variant has been reported in 7 individuals with clinical feature s of Noonan syndrome (Tartaglia 2006, Pierpont 2009, LMM data) and was absent fr om large population studies. Computational prediction tools and conservation ana lysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, two amino aci d changes at this position (p.Asn308Ser, p.Asn308Asp) are well established patho genic variants for Noonan syndrome further suggesting that a change at this posi tion may not be tolerated. In summary, this variant meets our criteria to be cla ssified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon frequency in probands and absence from controls. -

Aug 14, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.923A>C;p.Asn308Thr variant has been described in several individuals with a clinical diagnosis of Noonan syndrome (Ndiaye 2014, Pierpont 2009, Tartaglia 2006). The variant is listed in the ClinVar database (Variation ID: 40535) and the dbSNP variant database (rs121918455) but not described in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Ndiaye R et al. Mutation N308T of protein tyrosine phosphatase SHP-2in two Senegalese patients with Noonan syndrome. J Med Genet Gen. 2014 6(1): 6-10. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. 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. -

RASopathy

Pathogenic:2

Jan 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn308 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 19077116, 21340158; s16358218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 40535). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 28921562, 28991257). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 308 of the PTPN11 protein (p.Asn308Thr). -

Oct 22, 2019

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.923A>C (p.Asn308Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase (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 251440 control chromosomes (gnomAD). c.923A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Tartaglia_2006, Lee_2008, Pierpont_2009, Wilbe_2017). These data indicate that the variant is very likely to be associated with disease. In addition, other variants at the same codon have been reported to be associated with Noonan Syndrome, indicating it as a hotspot. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

LEOPARD syndrome 1

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP3_Strong+PM5_Strong+PP2 -

Noonan syndrome 1

Pathogenic:1

Aug 05, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Pathogenic:1

Dec 20, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS1,PM2,PM7,PP3,PP5 -

PTPN11-related disorder

Pathogenic:1

Jan 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.923A>C variant is predicted to result in the amino acid substitution p.Asn308Thr. This variant has been reported in at least four individuals with Noonan syndrome (Tartaglia et al. 2005. PubMed ID: 16358218; Pierpont et al. 2008. PubMed ID: 19077116; Table S9 - Jin et al. 2017. PubMed ID: 28991257). Additionally, this variant has been reported in three affected fetuses with features consistent with Noonan syndrome (Lee et al. 2008. PubMed ID: 18759865; Wilbe et al. 2017. PubMed ID: 28921562). Both de novo inheritance and gonadal mosaicism have been documented (Wilbe et al. 2017. PubMed ID: 28921562; Table S9 - Jin et al. 2017. PubMed ID: 28991257). This variant has not been reported in a large population database, indicating this variant is rare. Different amino acid substitutions (p.Asn308Asp and p.Asn308Ser) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). This variant is interpreted as pathogenic. -

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

Pathogenic:1

Mar 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Sep 13, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N308T pathogenic mutation (also known as c.923A>C), located in coding exon 8 of the PTPN11 gene, results from an A to C substitution at nucleotide position 923. The asparagine at codon 308 is replaced by threonine, an amino acid with similar properties. In one study, this mutation was detected in an individual with a clinical diagnosis of Noonan syndrome (Pierpont EI, et al. Genes Brain Behav. 2009;8(3):275-82). This mutation was also described in two individuals who likely had clinical diagnoses of either Noonan syndrome or Leigus syndrome; however, clinical diagnoses were not confirmed (Tartaglia M et al. Am J Hum Genet. 2006; 78(2):279-290). The Asn308 residue has been presented as a mutational hot spot, and two different mutations located in this same residue, p.N308S and p.N308D, have been described in multiple individuals with Noonan syndrome (Qiu W, et al. BMC Struct. Biol. 2014;14():10); Tartaglia M, et al. Nat. Genet. 2001;29(4):465-8; Zenker M, et al. J. Pediatr. 2004;144(3):368-74). Based on the supporting evidence, p.N308T is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Uncertain

0.60

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

.;.;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;M;M

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.5

D;D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.99

D;P;.

Vest4

0.97

MutPred

0.93

Loss of catalytic residue at N308 (P = 0.0135);Loss of catalytic residue at N308 (P = 0.0135);Loss of catalytic residue at N308 (P = 0.0135);

MVP

0.94

MPC

0.84

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.77

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