rs397507501

chr12-112446385-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):c.124A>G(p.Thr42Ala) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.31

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 15 ACMG points.

• PM1: In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 126 pathogenic changes around while only 1 benign (99%) in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PTPN11
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 12-112446385-A-G is Pathogenic according to our data. Variant chr12-112446385-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112446385-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112446385-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.124A>G	p.Thr42Ala	missense_variant	2/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.124A>G	p.Thr42Ala	missense_variant	2/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics, Centre for Human Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.124A>G in Exon 2 of the PTPN11 gene that results in the amino acid substitution p.Thr42Ala was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has previously reported for patients with RASopathies by Digilio MC, et, al., 2012. Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al.,2008.) ClinVar has also classified this variant as Pathogenic (Variant ID: 40482). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2013	The Thr42Ala variant in PTPN11 has been reported in 10 individuals in the litera ture (Tartaglia 2002, Sarkozy 2003, Zenker 2004, Lee 2007, Shaw 2007, Martinelli 2008, Digilio 2012) and one individual in our laboratory with clinical features of Noonan syndrome. This variant was reported to have occurred de novo in at le ast one of these individuals (Digilio 2012). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Pathogenic, no assertion criteria provided	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 27, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 19, 2015	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005; Muller et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); 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: 16358218, 30417923, 30050098, 18372317, 23584145, 15987685, 25425531, 24803665, 21590266, 17661820, 28483241, 11992261, 22781091, 29988639, 29907801, 31219622, 31560489, 32164556, 31936901, 32668055, 29493581, 33258288, 32786180) -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2019	Variant summary: PTPN11 c.124A>G (p.Thr42Ala) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246614 control chromosomes (gnomAD). c.124A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome, including de novo cases (Tartaglia_2002, Sarkozy_2003, Zenker_2004, Lee_2007, VanTrier_2015, Tamura_2018, Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. This variant exhibits increased affinity for mono-Tyr(P) peptide and phosphopeptide (Keilhack_2005 and Martinelli_2008), which is believed to be one of the mechanisms of SHP2's functional dysregulation. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 42 of the PTPN11 protein (p.Thr42Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15001945, 16358218, 17661820, 21590266, 22781091). ClinVar contains an entry for this variant (Variation ID: 40482). 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: 15987685, 18372317, 23584145). For these reasons, this variant has been 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

Sep 17, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2019

The p.T42A pathogenic mutation (also known as c.124A>G), located in coding exon 2 of the PTPN11 gene, results from an A to G substitution at nucleotide position 124. The threonine at codon 42 is replaced by alanine, an amino acid with similar properties, and is located in the N-SH2 domain. This mutation has been reported in numerous individuals with Noonan syndrome, including at least two reportedly de novo cases (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Lee ST et al. Clin. Genet., 2007 Aug;72:150-5; van Nierop JWI et al. Int. J. Pediatr. Otorhinolaryngol., 2017 Jun;97:228-234). Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al. Hum. Mol. Genet., 2008 Jul;17:2018-29). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Uncertain	0.10
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.038	D
MutationAssessor	Benign	0.72	N;N;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D;D;.;.
REVEL	Pathogenic	0.79
Sift	Benign	0.10	T;T;.;.
Sift4G	Benign	0.077	T;T;.;T
Polyphen		0.60	P;P;.;.
Vest4		0.82
MutPred		0.84		Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);
MVP		0.95
MPC		1.2
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.81

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

Other links and lift over

dbSNP: rs397507501; hg19: chr12-112884189; COSMIC: COSV61008667;