NM_002834.5:c.211T>C

Variant names:

• chr12-112450391-T-C
• rs397507512
• NM_002834.5:c.211T>C

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.211T>C​(p.Phe71Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F71V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.01
• Publications: 47 publications found

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 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 27 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr12-112450391-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 181495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 12-112450391-T-C is Pathogenic according to our data. Variant chr12-112450391-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.211T>C	p.Phe71Leu	missense	Exon 3 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.211T>C	p.Phe71Leu	missense	Exon 3 of 16	NP_001317366.1
	PTPN11	NM_001374625.1		c.208T>C	p.Phe70Leu	missense	Exon 3 of 16	NP_001361554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.211T>C	p.Phe71Leu	missense	Exon 3 of 16	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.211T>C	p.Phe71Leu	missense	Exon 3 of 15	ENSP00000489597.1
	PTPN11	ENST00000392597.5	TSL:1	c.211T>C	p.Phe71Leu	missense	Exon 3 of 11	ENSP00000376376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461322 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111536

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Apr 08, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 32164556, 24803665, 22681964, 19737548, 18759865, 18286234, 16358218, 14644997, 25097206, 26918529, 32794475, 36349709, 38539499, 38798550, 36380727, 34680203, 37021926, 34714648, 12634870, 11992261, 16053901, 29493581, 9491886)

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.211T>C; p.Phe71Leu variant (rs397507512) has been reported as a germline variant in multiple individuals with Noonan syndrome (Musante 2003, Strullu 2014), and also as a somatic variant in cases of juvenile myeolmonocytic leukemia and related malignancies (Strullu 2014, Tartaglia 2003, Zhange 2011). This variant, like most PTPN11 pathogenic variants associated with Noonan syndrome and childhood malignancies, affects the N-terminal SH2 regulatory domain of the protein (Musante 2003), and multiple other variants affecting this amino acid and other nearby residues have also been reported as pathogenic, including p.Phe71Ile, p.Glu69Gln, p.Lys70Arg, and p.Ala72Gly (Niihori 2005, Musante 2003, Xu 2017, Tartaglia 2001). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and is classified as pathogenic/likely pathogenic in ClinVar (variant ID: 40499). Based on the available evidence, the p.Phe71Leu variant is classified as pathogenic.

Noonan syndrome 1 Pathogenic:1

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

PTPN11-related disorder Pathogenic:1

Jan 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTPN11 c.211T>C variant is predicted to result in the amino acid substitution p.Phe71Leu. This variant has been reported in individuals with Noonan syndrome (Musante et al. 2003. PubMed ID: 12634870; Athota et al. 2020. PubMed ID: 32164556), Noonan syndrome with juvenile myelomonocytic leukaemia (Strullu et al. 2014. PubMed ID: 25097206), and in prenatal cases with features consistent with Noonan syndrome (Lee et al. 2008. PubMed ID: 18759865; Hakami et al. 2016. PubMed ID: 26918529). A different variant that affects the same residue (c.211T>A, p.Phe71Ile) has also been reported in individuals with Noonan syndrome (Niihori et al. 2005. PubMed ID: 15834506). In ClinVar, the c.211T>C variant is listed as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40499/). The p.Phe71Leu variant has also been reported as a somatic change in individuals with hematologic malignancies (see for example - Loh et al. 2004. PubMed ID: 15385933; Tartaglia et al. 2005. PubMed ID: 15842656). This variant is interpreted as pathogenic.

Noonan syndrome Pathogenic:1

Apr 05, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe71Leu variant in PTPN11 has not been seen before in our laboratory; howev er it has been reported in the literature in clinical features of Noonan syndrom e and pediatric acute myeloid leukemia (AML; Musante 2003, Loh 2004, Chan 2006). The Phe71Leu variant has not been identified in large European American and Afr ican American populations by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/). This variant has also been identified as an acquired somati c mutation in patients with hematological malignancies (Tartaglia 2006, Tartagli a 2005, Loh 2004, Chan 2006). The majority of identified pathogenic variants in the PTPN11 gene are located in exon 3 and involve the amino acids preceding and following the Phe71 residue, affect the N-SH2 domain, and are gain-of-function/a ctivating variants. Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance.

Noonan syndrome 3 Pathogenic:1

Mar 27, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PTPN11 c.211T>C (p.Phe71Leu) variant located in the N-SH2 domain involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest has not been observed in 121630 control chromosomes (ExAC and publication controls). Multiple publications have cited the variant in affected individuals diagnosed with Noonan syndrome, pediatric acute myeloid leukemia (AML) or JMML (Juvenile Myelomonocytic Leukemia). The variant of interest has also been indicated as a somatic occurrence in multiple patients with the Leukemic presentation(s). It is important to note that somatic PTPN11 mutations have been reported to exist in up to 35% of patients with JMML while germline PTPN11 mutations cause Noonan syndrome. Furthermore, additonal variants causing the same missense change, c.213T>A and c.213T>G, or another missense change at this position, c.211T>A (p.Phe71Ile) have been reported in the pathogenic spectrum, therefore, indicating the location is important for protein function. In addition, multiple clinical diagnostic laboratories classify the variant as "likely pathogenic/pathogenic." No well-established functional studies supportive of a damaging effect on the protein product have been published. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "likely pathogenic."

RASopathy Pathogenic:1

Sep 21, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 12634870, 14644997, 18759865, 19737548, 25097206; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40499). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the PTPN11 protein in which a significant number of missense variants have been reported (PMID: 18470943). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine with leucine at codon 71 of the PTPN11 protein (p.Phe71Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.95		Loss of methylation at K70 (P = 0.0335)
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397507512; hg19: chr12-112888195; COSMIC: COSV61006422; COSMIC: COSV61006422;