chr12-112489080-T-A

Position:

• chr12-112489080-T-A

Variant summary

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

The NM_002834.5(PTPN11):​c.1504T>A​(p.Ser502Thr) 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. S502A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.67

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 (HGNC:):

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 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 chr12-112489080-T-G is described in Lovd as [Pathogenic].
• 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, 0.972
• PP5: Variant 12-112489080-T-A is Pathogenic according to our data. Variant chr12-112489080-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 13332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112489080-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1504T>A	p.Ser502Thr	missense_variant	13/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1516T>A	p.Ser506Thr	missense_variant	13/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1501T>A	p.Ser501Thr	missense_variant	13/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1513T>A	p.Ser505Thr	missense_variant	13/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1504T>A	p.Ser502Thr	missense_variant	13/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1516T>A	p.Ser506Thr	missense_variant	13/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.517T>A	p.Ser173Thr	missense_variant	5/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 18, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2023	Published functional studies demonstrate a significant increase in phosphatase activity compared wildtype (Niihori et al., 2005); 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: 16358218, 15240615, 27521173, 12739139, 34184824, 12325025, 24803665, 15834506, 21407260, 25862627, 19737548, 32164556) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 29, 2015

proposed classification - variant undergoing re-assessment, contact laboratory -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The PTPN11 c.1504T>A variant is predicted to result in the amino acid substitution p.Ser502Thr. This variant has been reported in at least eight unrelated individuals with Noonan syndrome (Maheshwari et al. 2002. PubMed ID: 12325025; van Trier et al. 2016. PubMed ID: 27521173; Athota et al. 2020. PubMed ID: 32164556) and has been shown to be a de novo event in two cases (Maheshwari et al. 2002. PubMed ID: 12325025). Additionally, different amino acid substitutions (p.Ser502Ala, p.Ser502Leu) affecting the same amino acid have been reported as pathogenic (Kratz et al. 2005. PubMed ID: 15928039; Bertola et al. 2006. PubMed ID: 17020470). This variant has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/13332/). 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. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 22, 2018

The p.Ser502Thr variant (rs121918458) has been reported in multiple patients diagnosed with Noonan syndrome (Niihori 2005, Tartaglia 2006, van Trier 2016, Yoshida 2004), and reported as a presumed de-novo variant (Joyce 2016, Kondoh 2003, Maheshwari 2002). The serine residue is located in the phospho-tyrosine phosphatase domain of PTPN11, and interacts with the N-SH2 domain to mediate regulatory inhibition (Hof 1998). Functional characterization of the p.Ser502Thr protein indicates increased catalytic activity of the phosphatase (Niihori 2005), consistent with the established disease mechanisms of Noonan syndrome. -

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

Oct 27, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.1504T>A (p.S502T) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a T to A substitution at nucleotide position 1504, causing the serine (S) at amino acid position 502 to be replaced by a threonine (T). 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 has been reported in multiple individuals with features consistent with PTPN11-related RASopathy, including multiple cases of reported de novo occurrence (Maheshwari, 2002; Yoshida, 2004; Tartaglia, 2006; van Trier, 2015; Athota, 2020; Orlova, 2024). Two other alterations at the same codon, c.1505C>T (p.S502L) and c.1504T>G (p.S502A), have been reported in association with PTPN11-related RASopathy (Bertola, 2006; Joyce, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2023

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 502 of the PTPN11 protein (p.Ser502Thr). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser502 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12325025, 15928039, 17020470, 18470943, 19020799, 27521173). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 13332). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12325025, 32164556). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.030	D;D;T
Polyphen		0.81	P;.;.
Vest4		0.73
MutPred		0.88		Loss of glycosylation at S502 (P = 0.0523);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.88

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: rs121918458; hg19: chr12-112926884; COSMIC: COSV61015981; COSMIC: COSV61015981;