chr12-112473040-T-C

Position:

chr12-112473040-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The NM_002834.5(PTPN11):c.853T>C(p.Phe285Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F285V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense, splice_region

Scores

Splicing: ADA: 0.9884

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 7.67

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr12-112477651-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 12-112473040-T-C is Pathogenic according to our data. Variant chr12-112473040-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 40528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112473040-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5 linkuse as main transcript	c.853T>C	p.Phe285Leu	missense_variant, splice_region_variant	7/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.853T>C	p.Phe285Leu	missense_variant, splice_region_variant	7/16	1	NM_002834.5	A1	Q06124-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436904

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716352

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.18e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. The 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: 0.93; 3Cnet: 0.76). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040528) and different missense changes at the same codon (p.Phe285Cys, p.Phe285Ile, p.Phe285Ser, p.Phe285Tyr, p.Phe285Val / ClinVar ID: VCV000013335, VCV000040527, VCV000040533, VCV000181499, VCV000636408) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 07, 2024	PS1, PS4, PM1, PM2, PP3, PP5 - Same amino acid change as a known pathogenic variant. Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Noonan syndrome. (PMID:32164556). -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2018	The PTPN11 c.853T>C; p.Phe285Leu variant (rs397507531) is reported in the literature in individuals affected with Noonan or Noonan-like syndrome (Ferrero 2008, Jafarov 2005, Tartaglia 2002). This variant is reported as pathogenic five times in ClinVar (Variation ID: 40528) and is absent from the general population (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Another variant, c.855T>G, which results in the same amino acid change at codon 285, has also been reported in individuals affected with Noonan syndrome (Hung 2007). The phenylalanine at codon 285 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be deleterious. Additional variants resulting in different amino acid changes at this codon (Phe285Cys, Phe285Ile, Phe285Ser) have also been reported in individuals with Noonan syndrome (Aoki 2008, Ferrero 2008, Hung 2007), suggesting a critical role for this residue in protein function. Based on the above information, this variant is considered pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Ferrero G et al. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. 2008;51(6):566-72. Hung C et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. Jafarov T et al. Noonan-like syndrome mutations in PTPN11 in patients diagnosed with cherubism. Clin Genet. 2005 Aug;68(2):190-1. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2022	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often 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: 24183200, 28483241, 17339163, 17222357, 15689434, 34136918, 24803665, 26918529, 23771920, 22848035, 19120036, 15996221, 19303148, 11992261, 11704759, 17056636, 16523510, 12960218, 16124853, 18854871, 17020470, 16377799, 12717436, 18678287, 18470943, 27619028, 26297936, 26249544, 21533187, 21500339, 21396583, 19467855, 19206169, 9222968, 8530013, 1543375, 4025385, 1258892, 4386970, 30417923, 30050098, 29907801, 31219622, 31560489, 31324109, 32565546, 33300679, 34134972, 27521173, 29493581) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PTPN11: PS1, PS2, PM2, PM5, PS4:Moderate, PP3 -

LEOPARD syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 15, 2021	- -

Metachondromatosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 06, 2023

- -

PTPN11-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2024

The PTPN11 c.853T>C variant is predicted to result in the amino acid substitution p.Phe285Leu. This variant has been reported in multiple individuals with Noonan Syndrome and in several cases it was determined to be de novo (see for examples Tartaglia et al. 2002. PubMed ID: 11992261; Nyström et al. 2009. PubMed ID: 19120036; van Trier et al. 2016. PubMed ID: 27521173). A different nucleotide substitution (c.855T>G) resulting in the same missense variant has been reported in multiple individuals with Noonan syndrome (Hung et al. 2007. PubMed ID: 17339163). Additionally, different missense variants affecting this amino acid (p.Phe285Ile, p.Phe285Val, p.Phe285Tyr, p.Phe285Ser, p.Phe285Cys) have been reported to be pathogenic (Ferrero et al. 2008. PubMed ID: 18678287; El Naofal et al. 2023. PubMed ID: 36703223; Yu et al. 2019. PubMed ID: 30896080; Tartaglia et al. 2002. PubMed ID: 11992261; Tartaglia et al. 2006. PubMed ID: 16358218). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40528). This variant is interpreted as pathogenic. -

Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 26, 2012

The p.Phe285Leu variant in PTPN11 has been associated with the clinical features of Noonan syndrome as well as Noonan-like/multiple giant-cell lesion syndrome ( Tartaglia 2002, Nystrom 2008, Jafarov 2005, Lee 2005, LMM unpublished data). Thi s variant has been observed to have occurred de novo in sporadic cases of Noonan syndrome. Furthermore, a different nucleotide substitution, c.855T>G, that resu lts in the same amino acid change has been identified in a sporadic case of Noon an syndrome (Hung 2007). Therefore, this variant meets our criteria to be classi fied as pathogenic. -

Noonan syndrome 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 15, 2016

Variant summary: The PTPN11 c.853T>C (p.Phe285Leu) variant involves the alteration of a conserved nucleotide at the end of the exon 7. 3/4 in silico tools predict a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. There are no published functional studies for this variant. However, this variant is located in the PTP domain (InterPro), which is known to be important for protein function. This variant is absent in 118444 control chromosomes and is reported as a pathogenic variant found in several patients with NS or NS-related syndrome. It has also been reported as a de novo variant multiple instances. A different nucleotide substitution, c.855T>G, that results in the same amino acid change has been identified in a sporadic case of Noonan syndrome (Hung_JFMA_2007) and is classified as pathogenic by two labs in ClinVar. In addition, other substitutions (F285C, F285I and F285S) have been reported at this codon in association with Noonan syndrome (Tartaglia et al., 2006; Ferrero et al., 2008; Tartaglia et al., 2002). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Disease Variant/Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2024

The c.853T>C (p.F285L) alteration is located in exon 7 (coding exon 7) of the PTPN11 gene. This alteration results from a T to C substitution at nucleotide position 853, causing the phenylalanine (F) at amino acid position 285 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been described in multiple individuals with a clinical diagnosis of Noonan syndrome (Tartaglia, 2002; Chinton, 2019) and in other patients with Noonan syndrome-like features (Jafarov, 2005; Nyström, 2009). Another nucleotide substitution within the same codon, c.855T>G, has also been observed to result in p.F285L, and has also been described in multiple individuals with a clinical diagnosis of Noonan syndrome (Hung, 2007; Athota, 2020). Furthermore, additional alterations affecting amino acid residue F285 (p.F285C, p.F285S, p.F285I) have been described in individuals with Noonan syndrome (Tartaglia, 2006; Ferrero, 2008; Essawi, 2013). This amino acid position is highly conserved in available vertebrate species. The p.F285L amino acid is located in the protein tyrosine phosphatase (PTP) functional domain of the SHP-2 protein, and is predicted to disrupt the interdomain interaction with the N-SH2 domain, which normally stabilizes the inactive conformation of the protein (Tartaglia, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is 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

Oct 31, 2018

- -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17339163, 18470943, 18678287). 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) did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 function. ClinVar contains an entry for this variant (Variation ID: 40528). This missense change has been observed in individuals with Noonan or Noonan-like syndrome (PMID: 11992261, 15689434, 15996221, 23771920). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the PTPN11 protein (p.Phe285Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

CardioboostCm

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;.;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.1

D;D;.

REVEL

Pathogenic

0.93

Sift

Benign

0.031

D;D;.

Sift4G

Uncertain

0.050

T;D;D

Polyphen

0.84

P;P;.

Vest4

0.86

MutPred

0.94

Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);

MVP

0.99

MPC

0.95

ClinPred

0.99

GERP RS

5.7

Varity_R

0.97

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over