12-112450398-C-T

Position:

• chr12-112450398-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000351677.7(PTPN11):​c.218C>T​(p.Thr73Ile) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 ENST00000351677.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 7.90

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 hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000351677.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112450397-AC-CT is described in ClinVar as [Pathogenic]. Clinvar id is 44604.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: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 12-112450398-C-T is Pathogenic according to our data. Variant chr12-112450398-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450398-C-T is described in Lovd as [Likely_pathogenic]. Variant chr12-112450398-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.218C>T	p.Thr73Ile	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.218C>T	p.Thr73Ile	missense_variant	3/16	1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PTPN11: PM1, PM2, PS2:Moderate, PS3:Moderate, PS4:Moderate, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 21, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	Published functional studies demonstrate the variant results in increased activity compared to wild type (PMID: 15987685); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35050212, 34850017, 32164556, 23832011, 23446178, 24803665, 24718990, 26286251, 15928039, 20383758, 30355600, 28106910, 26918529, 30050098, 30378271, 29907801, 31219622, 31560489, 32144894, 32901917, 28191889, 35792504, 34974531, 11992261, 9491886, 29493581, 16053901, 15987685) -

Noonan syndrome 1 Pathogenic:5 Other:1

not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 27, 2023	This heterozygous mis-sense variant is identified in a 3 month male with congenital heart disease, facial dysmorphism, FTT, juvenial myelomonocytic leukemia and echogenic kidney. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.95] predicts deleterious nature of this variant [PP3: Strong]. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 13334] with “conflicting interpretation of pathogenicity, ”Pathogenic (14); Uncertain Significance (1)” interpretation by multiple submitter [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000013334.14, PMID: 25097206, 23446178, and 20383758, PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Thr73Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044604.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3Cnet: 0.996, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PP2+PP3_Strong+PS4 -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2016	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, no assertion criteria provided	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 12, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2019	Variant summary: PTPN11 c.218C>T (p.Thr73Ile) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) 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 276806 control chromosomes. c.218C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Juvenile Myelomonocyttic Leukema (JMML) (Tartaglia_2002, Tartaglia_2003, Niihori_2005, Kratz_2005, Kosaki_2002, Jongmans_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced phosphatase activity of mutant SHP-2. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 25, 2023	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome, Noonan-syndrome associated myeloproliferative disorder (PMID: 11992261, 14644997, 15240615, 15928039, 17020470, 17339163, 20383758, 23446178, 23832011). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13334). 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. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 24718990). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 73 of the PTPN11 protein (p.Thr73Ile). -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 01, 2022

- -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 01, 2022

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2016

The p.T73I pathogenic mutation (also known as c.218C>T), located in coding exon 3 of the PTPN11 gene, results from a C to T substitution at nucleotide position 218. The threonine at codon 73 is replaced by isoleucine, an amino acid with similar properties. This mutation has been described in the literature in multiple individuals with Noonan syndrome (Tartaglia M, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Kosaki K, J. Clin. Endocrinol. Metab. 2002 Aug; 87(8):3529-33) as well as in Noonan patients with accompanying Myeloproliferative disorders (MPD) or Juvenile myelomonocytic leukemia (JMML) (Kratz CP, Blood 2005 Sep; 106(6):2183-5. T; Niihori T, J. Hum. Genet. 2005; 50(4):192-202). This alteration has also been reported as a somatic mutation in individuals with hematologic malignancies (Tartaglia M, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90). In addition, functional studies have shown a statistically significant increase in phosphatase activity in cells expressing the p.T73I mutation, when compared to wild-type (Niihori T, J. Hum. Genet. 2005; 50(4):192-202; Tartaglia M, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90). Based on the supporting evidence, p.T73I is interpreted as a disease-causing mutation. -

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

May 18, 2017

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.1	D;D;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.93
MutPred		0.79		Loss of ubiquitination at K70 (P = 0.0901);Loss of ubiquitination at K70 (P = 0.0901);Loss of ubiquitination at K70 (P = 0.0901);Loss of ubiquitination at K70 (P = 0.0901);
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.95
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: rs121918462; hg19: chr12-112888202; COSMIC: COSV61004896; COSMIC: COSV61004896;