chr12-112450497-A-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.317A>C(p.Asp106Ala) 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. 14/23 in silico tools predict a damaging 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. D106E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.32

Publications

25 publications found

Variant links:

COSMIC-nc: COSV100692441

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 Gene-Disease associations (from GenCC):

LEOPARD syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
metachondromatosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr12-112450497-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 978850.Status of the report is criteria_provided_single_submitter, 1 stars.

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 Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

PP5

Variant 12-112450497-A-C is Pathogenic according to our data. Variant chr12-112450497-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 40506.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.317A>C	p.Asp106Ala	missense_variant	Exon 3 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 link	c.317A>C	p.Asp106Ala	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1 link	c.317A>C	p.Asp106Ala	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:3

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

Jul 09, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes:PS3; PS4; PM1; PM2; PP2; PP3

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:3

Mar 04, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Common missense variant in PTPN11, observed in 2-5% of patients with Noonan syndrome with or without multiple giant-cell lesions (PMID: 18470943, 12717436, 17020470, 16358218, 17339163, 16990350, 19077116, 21204800, 33318624, 11992261); Not observed at significant frequency in large population cohorts (gnomAD); Located in the linker region between the NSH2 and C-SH2 domains of the SHP-2 protein encoded by PTPN11 (PMID: 15987685); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21204800, 22848035, 28607217, 22420426, 19737548, 16208280, 23584145, 18854871, 31292302, 34930662, 24803665, 19835954, 19077116, 16990350, 17339163, 16358218, 12960218, 23624134, 24451042, 21590266, 25862627, 12717436, 16053901, 17020470, 22488759, 26124496, 30050098, 30410095, 29907801, 32164556, 18286234, 33318624, 29493581, 18470943, 11992261, 36588761, 15987685, 16987887)

Feb 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PTPN11 c.317A>C; p.Asp106Ala variant (rs397507517) is reported in the literature in multiple individuals affected with Noonan syndrome (Bertelloni 2013, Hung 2007, Leach 2019, Pierpont 2009, Shaw 2007, Stevenson 2011, Tartaglia 2002). This variant is also reported in ClinVar (Variation ID: 40506), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 106 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show hyperactivation upon peptide addition (Keilhack 2005). Additionally, another variant at this codon (c.317A>G; p.Asp106Gly) has been reported in individuals with Noonan syndrome (Bertelloni 2013). Based on available information, the p.Asp106Ala variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. 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. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Leach NT et al. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019 Feb;21(2):417-425. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. Shaw AC et al. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32. Stevenson DA et al. Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet. 2011 Dec;80(6):566-73. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RASopathy

Pathogenic:3

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Variant classified using ACMG guidelines

Sep 26, 2021

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The inherited heterozygous missense variant c.317A>C (p.Asp106Ala) identified in exon 3 (of 16) of the PTPN11 gene is a known pathogenic variant that has been reported in multiple unrelated individuals affected with Noonan spectrum disorders (PMID: 32164556, 17339163, 29907801, 19077116,16990350, 21204800, 11992261). This variant is reported as Pathogenic in the ClinVar database by multiple independent laboratories (Variation ID:40506). This variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. In vitro functional analyses suggest that this variant (located in the linker region between the NSH2 and C-SH2 domains of the PTPN11 protein) results in an increased activity due to misfolding of the inter-SH2 domain linker (PMID:15987685, 18286234). Based on the available evidence, the inherited heterozygous c.317A>C (p.Asp106Ala) variant identified in the PTPN11 gene is reported as Pathogenic.

Oct 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 106 of the PTPN11 protein (p.Asp106Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 12717436, 18470943). ClinVar contains an entry for this variant (Variation ID: 40506). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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: 15987685, 18286234). For these reasons, this variant has been classified as Pathogenic.

Noonan syndrome

Pathogenic:2

Jun 25, 2015

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 20, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp106Ala variant in PTPN11 has been reported in >10 individuals with Noonan syndrome-related disorders and non-immune hydrops fetalis. It segregated with disease in 2 affected individuals from 1 family (Tartaglia 2002, Bertola 2006, Tartaglia 2006, Hung 2007, Shaw 2007, Pierpont 2009, Stevenson 2010, Leach 2019, Sparks 2019). It has additionally been observed at the Laboratory for Molecular Medicine in 7 individuals, 5 with Noonan syndrome-like features and 1 with pulmonary stenosis. The variant was found to be de novo in 1 case (LMM Data). This variant was also observed de novo in a patient with Noonan syndrome tested by GeneDx (Clinvar Variation ID: 40506, Accession: SCV000057388.14). It was absent from large population studies. In vitro functional studies provide some evidence that the p.Asp106Ala variant may impact protein function (Keilhack 2005, Chan 2008, Lee 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome-related disorders. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2, PP3, PS3_Supporting.

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Nov 01, 2018

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

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;.;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

M;M;.;M

PhyloP100

9.3

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.7

D;D;.;.

REVEL

Pathogenic

0.94

Sift

Benign

0.075

T;T;.;.

Sift4G

Uncertain

0.015

D;D;.;D

Vest4

0.85

ClinPred

0.98

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.81

gMVP

0.74

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over