12-112419116-C-T

Position:

• chr12-112419116-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_002834.5(PTPN11):​c.5C>T​(p.Thr2Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,376,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T2T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 1.91

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 11 ACMG points.

• 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.
• PP5: Variant 12-112419116-C-T is Pathogenic according to our data. Variant chr12-112419116-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112419116-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.5C>T	p.Thr2Ile	missense_variant	1/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.5C>T	p.Thr2Ile	missense_variant	1/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000291 AC: 4 AN: 1376032 Hom.: 0 Cov.: 30 AF XY: 0.00000295 AC XY: 2 AN XY: 679052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	research	Department of Paediatrics and Adolescent Medicine, The University of Hong Kong	Jun 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene, and have been associated with metachondromatosis (MIM#156250) and Noonan syndrome 1 (MIM#163950), respectively (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in individuals with Noonan syndrome. One individual was also reported with a high grade glioma (ClinVar, PMID: 30693642). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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: 0.21; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013349). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 19449407,25337068,25862627). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 13, 2024	Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2 -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 21, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant classified as Pathogenic and reported on 12-12-2018 by UCLA Laboratory Genetics and Genomics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2020	DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.5C>T, in exon 1 that results in an amino acid change, p.Thr2Ile. This sequence change has not been described in population databases gnomAD, ExAC). The p.Thr2Ile change has been reported in several individuals with Noonan syndrome. In two of these individuals, this sequence change was reported to be de novo (PMIDs: 12960218, 19449407, 25337068, 25862627). The p.Thr2Ile change affects a moderately conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. The p.Thr2Ile substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Pathogenic missense variants in the PTPN11 gene are predominantly missense in nature. This sequence change likely causes a disease phenotype, however functional studies have not been performed to prove this conclusively. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 16358218, 30050098, 29907801, 12960218, 20186801, 25862627, 19449407, 32963807, 25337068) -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2018	Variant summary: PTPN11 c.5C>T (p.Thr2Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 113882 control chromosomes (gnomAD and literature). c.5C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (Sarkozy_2003, Thiel_2009, Tartaglia_2006, Louati_2014, vanTrier_2015, Pierpont_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2 of the PTPN11 protein (p.Thr2Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 12960218, 19449407, 25337068, 25862627). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13349). 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%. For these reasons, this variant has been classified as Pathogenic. -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2016

The p.Thr2Ile variant in PTPN11 has been identified in 6 individuals with clinic al features of Noonan syndrome (Sarkozy 2003, Tartaglia 2006, Thiel 2009, Louati 2014, LMM unpublished data), and was reported to have occurred de novo in 2 of these individuals (Thiel 2009, Louati 2014). Data from large population studies is insufficient to assess the frequency of this variant (dbSNP rs267606990). In summary, this variant meets our criteria to be classified as pathogenic for Noon an syndrome in an autosomal dominant manner based upon de novo occurrences. -

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 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
CardioboostCm	Uncertain	0.80
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;.;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.31	N;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.044	D;D;.;.
Sift4G	Uncertain	0.014	D;D;.;D
Polyphen		0.19	B;B;.;.
Vest4		0.38
MutPred		0.73		Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);
MVP		0.95
MPC		1.2
ClinPred		0.88	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.40
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267606990; hg19: chr12-112856920;