12-112450391-T-C

Position:

• chr12-112450391-T-C

Variant summary

Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1 PM1 PM2 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. 14/22 in silico tools predict a damaging 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 Likely pathogenicin Lovd.

• 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

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 21 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
• 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, 0.985
• PP5: Variant 12-112450391-T-C is Pathogenic according to our data. Variant chr12-112450391-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450391-T-C is described in Lovd as [Likely_pathogenic]. Variant chr12-112450391-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.211T>C	p.Phe71Leu	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.211T>C	p.Phe71Leu	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.211T>C	p.Phe71Leu	missense_variant	3/15	5		ENSP00000489597.1

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

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 11, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2020	Not observed in large population cohorts (Lek et al., 2016); 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 (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32164556, 12634870, 24803665, 22681964, 19737548, 18759865, 18286234, 16358218, 14644997, 25097206, 26918529, 32794475) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

-

- -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2013

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 27, 2017

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 21, 2021

For these reasons, this variant has been classified as Pathogenic. 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. 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"). ClinVar contains an entry for this variant (Variation ID: 40499). 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. This variant is not present in population databases (ExAC no frequency). 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 v4.3

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;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;H;.;H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.4	D;D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.0050	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.90
MutPred		0.95		Loss of methylation at K70 (P = 0.0335);Loss of methylation at K70 (P = 0.0335);Loss of methylation at K70 (P = 0.0335);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

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