12-112450354-C-G

Position:

• chr12-112450354-C-G

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.174C>G​(p.Asn58Lys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N58D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.78

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 23 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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-G is described in Lovd as [Likely_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, 0.946
• PP5: Variant 12-112450354-C-G is Pathogenic according to our data. Variant chr12-112450354-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450354-C-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112450354-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.174C>G	p.Asn58Lys	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.174C>G	p.Asn58Lys	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.174C>G	p.Asn58Lys	missense_variant	3/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2024	Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; Not observed at significant frequency 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: 22190897, 26607044, 32164556, 12634870, 23321623, 25914815, 24803665, 28425981, 16358218, 15928039, 20954246, 15723289, 18286234, 30417923, 30050098, 29907801, 35979676, 11992261, 9491886, 16053901, 29493581) -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 22, 2022	The c.174C>G, p.Asn58Lys variant in PTPN11 has been reported in at least 6 individuals with clinical features of Noonan syndrome and segregated with disease in at least 4 affected relatives from one family (Musant 2003 PMID:12634870, Tartaglia 2006 PMID:16358218, Derbent 2010 PMID:20954246, Digilio 2011 PMID:22190897, Croonen 2013 PMID:23321623, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 40489) and absent from large population studies. Computational tools and conservation analyses are consistent with pathogenicity. Another variant resulting in the same missense change (c.172A>C, p.Asn58His) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have also been reported in ClinVar as a Pathogenic variant by several clinical laboratories, including this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PS4, PP1, PM2_Supporting, PM5_strong, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2017	Variant summary: The PTPN11 c.174C>G (p.Asn58Lys) variant located in the mutational hotspot, SH2 domain, involves the alteration of a non-conserved nucleotide and by 4/4 in-silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 122184 control chromosomes including broad and large populations from ExAC. Publications have cited this variant as a pathogenic variant and has been detected in several patients with Noonans syndrome, including multiple instances of a de novo origin (Musante_2003, Tartaglia_2006, Derbent_2010, Digilio_2011, Ezquieta_2012, Croonen_2012, Coromilas_2015, and Cizmarova_2015). Other missense variants at this residue (N58Y, N58D, N58H, and N58S) are reported in association with Noonan syndrome and are classified as pathogenic/likely pathogenic by submitters in ClinVar, strongly suggesting that the codon itself is a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 12634870, 20954246, 22190897, 23321623). ClinVar contains an entry for this variant (Variation ID: 40489). 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 with a positive predictive value of 95%. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15001945, 16263833, 19125092). 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. -

Noonan syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Dec 04, 2012

- -

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

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.17
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.49	N;N;.;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.4	D;D;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0050	D;D;.;.
Sift4G	Benign	0.11	T;T;.;T
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.90		Gain of methylation at N58 (P = 0.0017);Gain of methylation at N58 (P = 0.0017);Gain of methylation at N58 (P = 0.0017);Gain of methylation at N58 (P = 0.0017);
MVP		0.90
MPC		2.1
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs397507506; hg19: chr12-112888158; COSMIC: COSV61010683; COSMIC: COSV61010683;