12-112477720-A-G

Position:

• chr12-112477720-A-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000351677.7(PTPN11):​c.923A>G​(p.Asn308Ser) 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. N308D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 ENST00000351677.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:37 O:1
• Conservation: PhyloP100: 8.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 131 pathogenic changes around while only 10 benign (93%) in ENST00000351677.7
• 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 ClinVar as [Pathogenic]. Clinvar id is 13326.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ 3.1293 (greater than the threshold 3.09). Trascript score misZ 4.9438 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.982
• PP5: Variant 12-112477720-A-G is Pathogenic according to our data. Variant chr12-112477720-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112477720-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.923A>G	p.Asn308Ser	missense_variant	8/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.923A>G	p.Asn308Ser	missense_variant	8/16	1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:37 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Dec 03, 2020	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 31, 2021	The PTPN11 c.923A>G variant is classified as a PATHOGENIC variant (PS1, PS3, PS4, PP3) The variant is a single nucleotide change from an adenine to a guanine at position 923 which is predicted to change the Asparagine at position 308 in the protein to Serine. The variant is in exon 8 and is located in protein domains: protein-tyrosine phosphatase (receptor/non-receptor type) of the PTPN11 gene. This variant is a recurrent PTPN11 variant, previously reported in on patient in our laboratory and in multiple individuals with Noonan syndrome across multiple publications, including Tartaglia et al., 2002 (PMID: 11992261) (PS4). This variant is in dbSNP (rs121918455) but is absent from population databases. Other variants at this codon (p.Asn308Asp, p.Asn308Thr) have been previously reported in individuals with Noonan syndrome and are considered pathogenic (PS1). In vitro functional studies have shown that this variant alters substrate specificity and increased catalytic activity relative to the wildtype protein (PMID:15987685) (PS3). The vaviants has been reported in ClinVar (Variation ID: 13327) and HGMD (Accession: CM021135) as pathogenic. Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 11992261) within the protein tyrosine phosphatase domain (PMID: 26817465). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes, p.(Asn308Asp) and p.(Asn308Thr), have been reported in multiple individuals with Noonan syndrome 1 (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most commonly reported variants in this gene in individuals with Noonan syndrome 1. (SP) 1102 - Strong phenotype match for this individual. (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 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013327, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326,VCV000040535, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.685, 3CNET: 0.94, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	May 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 04, 2015	This variant identified in a very young patient diagnosed with the Noonan syndrome has already been reported to cause this syndrome. -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 29, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2023	The PTPN11 c.923A>G; p.Asn308Ser variant (rs121918455) is reported in the literature in numerous individuals affected with Noonan syndrome (Demir 2010, Ezquieta 2012, Lee 2011, Lepri 2014, Tartaglia 2006, Tartaglia 2002, Xu 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13327) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional analyses demonstrate that the Asn308Ser variant has altered substrate specificity and increased catalytic activity relative to the wildtype protein (Keilhack 2005), consistent with established disease mechanisms of Noonan syndrome (Tartaglia 2001). Additionally, other variants at this codon (c.922A>G; p.Asn308Asp, c.923A>C; p.Asn308Thr) have been reported in individuals with Noonan syndrome and are considered pathogenic (Ezquieta 2012, Lee 2011, Lepri 2014, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006). Based on available information, the p.Asn308Ser variant is considered pathogenic. REFERENCES Demir K et al. A mother and son with Noonan syndrome resulting from a PTPN11 mutation: first report of molecularly proven cases from Turkey. Turk J Pediatr. 2010 May-Jun;52(3):321-4 Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Lee BH et al. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr. 2011 Dec;159(6):1029-35. Lepri FR et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. 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. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. 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. Xu S et al. Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders. BMC Med Genomics. 2017 Oct 30;10(1):62. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2022	Published functional studies demonstrate a damaging effect showing that the variant impacts substrate specificity of the catalytic site (Keilhack et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 30417923, 32369273, 18854871, 11992261, 27626068, 26918529, 11704759, 26817465, 25912702, 29084544, 28991257, 30050098, 20718194, 30842647, 29907801, 31219622, 31560489, 32164556, 31370276, 32037394, 15987685, 33686258, 33318624, 33300679, 33673806, 32368696, 33442022, 29493581, 16053901, 9491886) -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Aug 05, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2015	- -

Noonan syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Donald Williams Parsons Laboratory, Baylor College of Medicine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 13, 2013	The p.Asn308Ser variant has previously been associated with the clinical feature s of Noonan syndrome and Noonan syndrome associated with multiple giant-cell les ions in bone (Ko 2008, Tartaglia 2002, Pierpont 2009, Sarkozy 2003, Tartaglia 20 05). This variant has been observed to have occurred de novo in sporadic cases a nd to segregate with clinical features in familial cases. Variants affecting pos ition 308 (p.Asn308Ser and p.Asn308Asp) are the most frequently identified patho genic PTPN11 mutations in individuals with clinical features of Noonan syndrome in our laboratory. In summary, this variant meets our criteria to be classified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon seg regation studies, de novo occurrence, and absence from controls. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 03, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 08, 2017	- -

LEOPARD syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PP2,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense c.923A>G (p.Asn308Ser) variant in PTPN11 gene has been reported in heterozygous state in multiple individuals affected with PTPN11-related disorders (Digilio et al., 2013; Lepri et al., 2014; Loddo et al., 2015). It has also been observed to segregate with disease in related individuals (Digilio et al., 2013). Functional studies demonstrate a damaging effect showing that the variant impacts substrate specificity of the catalytic site (Keilhack et al., 2005). This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Asn308Ser in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 308 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic -

PTPN11-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 05, 2020	This variant has been observed as a heterozygous change in multiple individuals with Noonan Syndrome and shown to segregate with disease in several families (PMID: 11992261, 20718194, 25912702, 24451042, 29907801). Functional studies of p.Asn308Ser have shown that it alters substrate specificity at the catalytic site (PMID: 15987685). A different missense substitution at this codon (p.Asn308Asp) has also been determined to be pathogenic (PMID: 11992261). ClinVar contains an entry for this variant (Variation ID: 13327).It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.923A>G, p.Asn308Ser variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 14, 2024	The PTPN11 c.923A>G variant is predicted to result in the amino acid substitution p.Asn308Ser. This variant has been well-documented to be causative for Noonan Syndrome (see for example - Tartaglia et al. 2002. PubMed ID: 11992261). This variant was found to segregate in a large multi-generation pedigree (Tartaglia et al. 2002. PubMed ID: 11992261) and has been reported as a de novo variant in an individual with congenital heart defects (Jin et al. 2017. PubMed ID: 28991257, Table S9). Functional studies of this variant demonstrate increased catalytic activity and altered substrate specificity compared to wild type PTPN11 (Keilhack et al. 2005. PubMed ID: 15987685). Additionally, different amino acid substitutions (p.Asn308Asp, p.Asn308Thr) affecting the same amino acid 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 has been interpreted as pathogenic by multiple clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/13327/). This variant is interpreted as pathogenic. -

RASopathy Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 308 of the PTPN11 protein (p.Asn308Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 19077116, 20718194, 22781091, 24451042, 25595571). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13327). 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%. 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). 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. -

LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jun 27, 2019

- -

Noonan syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 23, 2016

Variant summary: The PTPN11 c.923A>G (p.Asn308Ser) variant involves the alteration of a conserved nucleotide. Residue Asn308 is buried within the PTP domain, and is reported as the most common residue affected in NS patients(N308D and N308S). 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). However, functional assays suggest that this variant alters substrate specificity (Keilhack_JBC_2005), and N308S SHP-2-expressing fetal liver cells also displayed a hypersensitive pattern of CFU-GM colony growth in response to GM-CSF (Schubbert_Blood_2005). This variant has been reported in numerous patients with NS and related conditions and was absent in 122002 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.83	L;L;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.072	T;T;.
Sift4G	Benign	0.39	T;T;T
Polyphen		0.34	B;B;.
Vest4		0.89
MutPred		0.92		Loss of stability (P = 0.0668);Loss of stability (P = 0.0668);Loss of stability (P = 0.0668);
MVP		0.87
MPC		0.65
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121918455; hg19: chr12-112915524; COSMIC: COSV61006976; COSMIC: COSV61006976;