12-112477651-T-C

Position:

• chr12-112477651-T-C

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.854T>C​(p.Phe285Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F285L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense, splice_region
• Scores: Splicing: ADA: 0.8010
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30 O:1
• Conservation: PhyloP100: 5.89

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 chr12-112473040-T-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, 0.991
• PP5: Variant 12-112477651-T-C is Pathogenic according to our data. Variant chr12-112477651-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112477651-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.854T>C	p.Phe285Ser	missense_variant, splice_region_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.854T>C	p.Phe285Ser	missense_variant, splice_region_variant	8/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.854T>C	p.Phe285Ser	missense_variant, splice_region_variant	8/15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2022	PP2, PP3, PM2, PM6_strong, PS3_supporting, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2020	Published X-ray crystallography studies showed the variant causes conformational changes, and functional in vitro studies demonstrated modestly increased basal phosphatase activity; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21901340, 30266093, 11992261, 24183200, 21106241, 24803665, 29907801, 12161469, 26918529, 30732632, 30050098, 31219622, 27030275, 32164556, 32668031) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Sep 23, 2022	PP3, PS1, PM5, PP2, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PTPN11: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Noonan syndrome 1 Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	Jun 22, 2022	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Mar 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 16, 2022	The PTPN11 c.854T>C variant is a single nucleotide change in exon 8/16 of the PTPN11 gene, which is predicted to change the amino acid phenylalanine at position 285 in the protein to serine. This variant has been identified as a de novo variant in this fetus (PS2). The variant has been reported in 12 probands with a clinical presentation of Noonan Syndrome (e.g. PMID: 11992261; PMID:24183200) (PS4). This variant is absent from population databases (PM2). This is a missense variant in a constrained region of the PTPN11 gene, where missense variants are a common mechanism of disease and benign variation is rare (PP2). This variant is a missense change at an amino acid residue where many different missense changes have been seen before, and associated with disease (e.g. PMID: 23321623) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs121918463) and in the HGMD database: CM021134. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 13335). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013335 / PMID: 11992261 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Phe285Cys, p.Phe285Ile, p.Phe285Leu, p.Phe285Tyr, p.Phe285Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040527, VCV000040528, VCV000040533, VCV000044615, VCV000181499, VCV000636408, VCV001201246 / PMID: 11992261, 16358218, 17339163, 18678287, 30896080 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PM6_Strong+PM5+PP2+PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2024	- -

Noonan syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 27, 2019	The p.Phe285Ser variant in PTPN11 has been reported in the literature in several individuals with the clinical features of Noonan syndrome, and has been shown to have arisen as a de novo event in some of these individuals (Aoki 2008, Tartaglia 2006, Kosaki 2002, Park 2012, Essawi 2013, LMM data). This variant was absent from large population studies. In addition, several other amino acid changes at this position (p.Phe285Cys, p.Phe285Leu) have also been reported in individuals with Noonan spectrum features. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP codes applied: PS4, PM2, PM5_Strong, PM6_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 25, 2015	- -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the PTPN11 protein (p.Phe285Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 15240615, 18470943, 19020799, 21106241, 23321623, 24183200). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13335). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 27030275). 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: 11992261, 16358218, 18470943). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2018	Variant summary: PTPN11 c.854T>C (p.Phe285Ser) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246952 control chromosomes (gnomAD). The variant, c.854T>C, has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Tartaglia_2006, Kosaki_2002, Croonen_2013, Lee_2011, ssawi_2013, Bertola_2006, Prontera_2013). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. In addition, other missense mutations at this position, Phe285Cys and Phe285Leu, have been reported to be pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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 de novo change in patients with Noonan Syndrome (PMID: 11992261, 18470943, 24183200, 19020799, 15240615,23321623, 21106241 ). Different amino acid changes at the same residue (p.Phe285Cys, p.Phe285Leu) have been previously reported in individuals with Noonan Syndrome (PMID: 16358218, 18470943, 11992261). The PTPN11 gene is highly constrained (Z-score= 3.13 and pLI = 1), which suggests it is intolerant to variation. It was illustrated that the c.854T>C (p.Phe285Ser) variant increases PTPN11 basal activity and sensitivity to ligand stimulation (PMID: 27030275). The c.854T>C (p.Phe285Ser) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.854T>C (p.Phe285Ser) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. 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.854T>C (p.Phe285Ser) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 11, 2023	The PTPN11 c.854T>C variant is predicted to result in the amino acid substitution p.Phe285Ser. This variant has been reported in at least four unrelated individuals with Noonan syndrome (Tartaglia et al. 2002. PubMed ID: 11992261; Yoshida et al. 2004. PubMed ID: 15240615; Ko et al. 2008. PubMed ID: 19020799; Essawi et al. 2013. PubMed ID: 24183200), two fetal cases suggestive of Noonan syndrome (Croonen et al. 2013. PubMed ID: 23321623; Normand. 2018. PubMed ID: 30266093), and in a case of syndromic juvenile myelomonocitic leukemia (JMML) (Prontera et al. 2011. PubMed ID: 21106241). In at least three of these cases the variant was likely de novo (Prontera et al. 2011. PubMed ID: 21106241; Croonen et al. 2013. PubMed ID: 23321623; Normand. 2018. PubMed ID: 30266093). Functional studies demonstrate the p.Phe285Ser leads to an increase in basal PTPN11 activity and increased sensitivity to ligand stimulation (LaRochelle et al. 2016. PubMed ID: 27030275). Additionally, different amino acid substitutions affecting the same amino acid (p.Phe285Leu, p.Phe285Cys) have been reported in individuals with Noonan syndrome (Human Gene Mutation Database). At PreventionGenetics, we previously identified this variant in other individuals with Noonan syndrome. This variant has been interpreted as pathogenic by multiple clinical labs in ClinVar. This variant is interpreted as pathogenic. -

Early T cell progenitor acute lymphoblastic leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Center for Advanced Molecular Diagnostics, Cytogenetics Laboratory, Brigham and Women's Hospital

-

Activating PTPN11 mutation found in ETP-ALL, juvenile myelomonocytic leukemia, and Noonan syndrome -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2024

- -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2024

- -

Non-immune hydrops fetalis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Apr 23, 2020

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.018	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.95		Gain of disorder (P = 0.0032);Gain of disorder (P = 0.0032);Gain of disorder (P = 0.0032);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Pathogenic	0.80
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: rs121918463; hg19: chr12-112915455; COSMIC: COSV61005134; COSMIC: COSV61005134;