12-112450352-A-G

Position:

• chr12-112450352-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 NM_002834.5(PTPN11):​c.172A>G​(p.Asn58Asp) 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. N58H) 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:22
• Conservation: PhyloP100: 9.31

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 19 ACMG points.

• PM1: In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) 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 chr12-112450352-A-C 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, 0.971
• PP5: Variant 12-112450352-A-G is Pathogenic according to our data. Variant chr12-112450352-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 40487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450352-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112450352-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.172A>G	p.Asn58Asp	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.172A>G	p.Asn58Asp	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.172A>G	p.Asn58Asp	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	May 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2023	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 26, 2021	ACMG codes:PS2; PS4M; PM1; PP2; PP3; PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 24, 2022	The PTPN11 c.172A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid asparagine at position 58 in the protein to aspartic acid. This variant has been identified as a de novo variant in this fetus (PS2). The variant has been reported in 8 probands with a clinical presentation of Noonan Syndrome (e.g. PMID: 15001945; PMID: 16804314) (PS4). This variant is absent from population databases (PM2). This variant is a missense change at an amino acid residue where multiple different missense changes have been seen before in association with disease (e.g. PMID: 12634870) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397507505) and in the HGMD database: CM044250. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40487). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. he variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040487). Different missense changes at the same codon (p.Asn58His, p.Asn58Lys, p.Asn58Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040486, VCV000040488, VCV000040489, VCV000181494). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, 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) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 103 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Asn58His) has been well reported as pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic by more than ten accredited laboratories in ClinVar. (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 -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PTPN11: PM1, PM2, PM5, PM6, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 12, 2019	DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.172A>G, in exon 3 that results in an amino acid change, p.Asn58Asp. This sequence change is not present in large population databases such as ExAC and gnomAD. The p.Asn58Asp change affects a moderately conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn58Asp substitution. This variant has been reported in several individuals with a clinical diagnosis of Noonan syndrome, occurring de novo in at least 3 of these individuals (PMID:15001945, PMID:15956085, PMID:18678287, PMID:19077116, PMID:20030748, PMID:21590266). Furthermore, missense variants affecting the same amino acid residue (p.Asn58Lys and p.Asn58His) and nearby residues have also been reported in association with Noonan syndrome supporting the functional importance of protein domain (PMID: 12634870, PMID: 16263833). This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19077116, 16804314, 32164556, 32059087, 19125092, 24803665, 15956085, 26918529, 15001945, 20030748, 18678287, 30693642, 30556322, 33144682, 33726816, 11992261, 16053901, 29493581, 9491886) -

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	-	This variant has been previously reported as a heterozygous change in patients with Noonan syndrome, including several individuals in whom the variant was reported as a de novo change (PMID: 19125092, 21590266, 15001945, 16804314, 15956085, 18678287, 19077116, 20030748, 32164556). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with Noonan syndrome (PMID: 11992261). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.172A>G (p.Asn58Asp) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 24, 2023	The PTPN11 c.172A>G variant is predicted to result in the amino acid substitution p.Asn58Asp. This variant has been reported in multiple individuals with Noonan syndrome including at least one report of it occurring de novo (see for example - Zenker et al. 2004. PubMed ID: 15001945; Kitsiou-Tzeli et al. 2006. PubMed ID: 16804314; Hakami et al. 2016. PubMed ID: 26918529). Additionally, different missense variants affecting this amino acid (p.Asn58His, p.Asn58Tyr, p.Asn58Ser, p.Asn58Lys) 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 is interpreted as pathogenic. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2017	Variant summary: The PTPN11 c.172A>G (p.Asn58Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant has been reported in multiple patients with Noonan syndrome and is absent in 277532 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 40487). This missense change has been observed in individual(s) with clinical features or diagnoses of Noonan syndrome (PMID: 15001945, 15956085, 16804314, 19077116, 19125092, 21590266). 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 aspartic acid, which is acidic and polar, at codon 58 of the PTPN11 protein (p.Asn58Asp). -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 24, 2023

- -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 24, 2023

- -

Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Dec 01, 2023

- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2014

The Asn58Asp variant in PTPN11 has previously been identified in >10 individuals with clinical features of Noonan syndrome, including at least 3 individuals whe re the variant was reported to have occurred de novo (Zenker 2004, Ferrero 2008, Ferreira 2005, Kitsiou-Tzeli 2006, Pierpont 2009, Tumurkhuu 2010, LMM unpublish ed data). This variant was not identified in large population studies. In summar y, this variant meets our criteria to be classified as pathogenic (http://pcpgm. partners.org/LMM). -

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

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

PTPN11 NM_002834.4 exon 3 p.Asn58Asp (c.172A>G): This variant has been reported in the literature in at least 6 individuals with Noonan syndrome, occuring de novo in at least 3 of these individuals (Zenker 2004 PMID:15001945, Ferreira 2005 PMID:15956085, Ferrero 2008 PMID:18678287, Pierpont 2009 PMID:19077116, Tumurkhuu 2010 PMID:20030748, Papadopolou 2012 PMID:21590266). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40487). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, this variant occurs within the N-SH2 domain, a critical region for the function of this gene, and increases the likelihood that this variant is damaging (Tartaglia 2002 PMID: 11992261, Strullu 2014 PMID:25097206). Furthermore, two other variants at this position (p.Asn58His and p.Asn58Lys) have also been reported in association with disease, supporting that this region has significance. In summary, this variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.172A>G (p.N58D) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from an A to G substitution at nucleotide position 172, causing the asparagine (N) at amino acid position 58 to be replaced by an aspartic acid (D). 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 was determined to be de novo in at least one individual with features consistent with PTPN11-related RASopathy (Ferreira, 2005; Kitsiou-Tzeli, 2006). This amino acid position is highly conserved in available vertebrate species. This variant is located in a mutation hotspot in the N-terminal Src homology 2 domain and is indicated to be structurally deleterious (Ambry internal data; Russo, 1998). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.73
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	.;.;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.3	L;L;.;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.018	D;D;.;.
Sift4G	Uncertain	0.024	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.92
MutPred		0.93		Loss of methylation at K55 (P = 0.1138);Loss of methylation at K55 (P = 0.1138);Loss of methylation at K55 (P = 0.1138);Loss of methylation at K55 (P = 0.1138);
MVP		0.90
MPC		2.0
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.75

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: rs397507505; hg19: chr12-112888156;