rs121918455

Positions:

• chr12-112477720-A-C
• 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 NM_002834.5(PTPN11):​c.923A>C​(p.Asn308Thr) 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 Likely 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 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• 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 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 chr12-112477719-A-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, 0.994
• PP5: Variant 12-112477720-A-C is Pathogenic according to our data. Variant chr12-112477720-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.923A>C	p.Asn308Thr	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>C	p.Asn308Thr	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/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PTPN11: PS2, PM2, PM5, PP3, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 14, 2023	PP2, PP3, PM1, PM2_supporting, PS2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2021	Identified in patients with cystic hygroma and other abnormal ultrasound findings in published literature (Wilbe et al., 2017; Lee et al., 2009); 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: 18759865, 29057136, 15001945, 24803665, 28921562, 28991257, 19077116, 33318624, 32978145, 32368696, 11992261, 9491886, 16053901, 29493581) -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 14, 2017	The PTPN11 c.923A>C;p.Asn308Thr variant has been described in several individuals with a clinical diagnosis of Noonan syndrome (Ndiaye 2014, Pierpont 2009, Tartaglia 2006). The variant is listed in the ClinVar database (Variation ID: 40535) and the dbSNP variant database (rs121918455) but not described in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Ndiaye R et al. Mutation N308T of protein tyrosine phosphatase SHP-2in two Senegalese patients with Noonan syndrome. J Med Genet Gen. 2014 6(1): 6-10. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2016	The p.Asn308Thr variant has been reported in 7 individuals with clinical feature s of Noonan syndrome (Tartaglia 2006, Pierpont 2009, LMM data) and was absent fr om large population studies. Computational prediction tools and conservation ana lysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, two amino aci d changes at this position (p.Asn308Ser, p.Asn308Asp) are well established patho genic variants for Noonan syndrome further suggesting that a change at this posi tion may not be tolerated. In summary, this variant meets our criteria to be cla ssified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon frequency in probands and absence from controls. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2019	Variant summary: PTPN11 c.923A>C (p.Asn308Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). c.923A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Tartaglia_2006, Lee_2008, Pierpont_2009, Wilbe_2017). These data indicate that the variant is very likely to be associated with disease. In addition, other variants at the same codon have been reported to be associated with Noonan Syndrome, indicating it as a hotspot. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2022	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. For these reasons, this variant has been classified as Pathogenic. 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, 19077116, 21340158; s16358218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 40535). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 28921562, 28991257). 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 threonine, which is neutral and polar, at codon 308 of the PTPN11 protein (p.Asn308Thr). -

Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Aug 05, 2024

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

ACMG categories: PS1,PM2,PM7,PP3,PP5 -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2024

The PTPN11 c.923A>C variant is predicted to result in the amino acid substitution p.Asn308Thr. This variant has been reported in at least four individuals with Noonan syndrome (Tartaglia et al. 2005. PubMed ID: 16358218; Pierpont et al. 2008. PubMed ID: 19077116; Table S9 - Jin et al. 2017. PubMed ID: 28991257). Additionally, this variant has been reported in three affected fetuses with features consistent with Noonan syndrome (Lee et al. 2008. PubMed ID: 18759865; Wilbe et al. 2017. PubMed ID: 28921562). Both de novo inheritance and gonadal mosaicism have been documented (Wilbe et al. 2017. PubMed ID: 28921562; Table S9 - Jin et al. 2017. PubMed ID: 28991257). This variant has not been reported in a large population database, indicating this variant is rare. Different amino acid substitutions (p.Asn308Asp and p.Asn308Ser) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). This variant is interpreted 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

Mar 14, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2015

The p.N308T pathogenic mutation (also known as c.923A>C), located in coding exon 8 of the PTPN11 gene, results from an A to C substitution at nucleotide position 923. The asparagine at codon 308 is replaced by threonine, an amino acid with similar properties. In one study, this mutation was detected in an individual with a clinical diagnosis of Noonan syndrome (Pierpont EI, et al. Genes Brain Behav. 2009;8(3):275-82). This mutation was also described in two individuals who likely had clinical diagnoses of either Noonan syndrome or Leigus syndrome; however, clinical diagnoses were not confirmed (Tartaglia M et al. Am J Hum Genet. 2006; 78(2):279-290). The Asn308 residue has been presented as a mutational hot spot, and two different mutations located in this same residue, p.N308S and p.N308D, have been described in multiple individuals with Noonan syndrome (Qiu W, et al. BMC Struct. Biol. 2014;14():10); Tartaglia M, et al. Nat. Genet. 2001;29(4):465-8; Zenker M, et al. J. Pediatr. 2004;144(3):368-74). Based on the supporting evidence, p.N308T is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Uncertain	0.60
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;.;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;P;.
Vest4		0.97
MutPred		0.93		Loss of catalytic residue at N308 (P = 0.0135);Loss of catalytic residue at N308 (P = 0.0135);Loss of catalytic residue at N308 (P = 0.0135);
MVP		0.94
MPC		0.84
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.77

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: rs121918455; hg19: chr12-112915524; COSMIC: COSV61014185; COSMIC: COSV61014185;