12-112419116-C-T

Variant names:

• chr12-112419116-C-T
• rs267606990
• NM_002834.5:c.5C>T

Variant summary

Our verdict is Pathogenic. The variant received 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:19 O:1
• Conservation: PhyloP100: 1.91
• Publications: 11 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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.5C>T	p.Thr2Ile	missense_variant	Exon 1 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.5C>T	p.Thr2Ile	missense_variant	Exon 1 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.5C>T	p.Thr2Ile	missense_variant	Exon 1 of 15	5		ENSP00000489597.1

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

⚠️ 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: 29122

American (AMR) AF: 0.00 AC: 0 AN: 34638

Ashkenazi Jewish (ASJ) AF: 0.0000406 AC: 1 AN: 24608

East Asian (EAS) AF: 0.00 AC: 0 AN: 34042

South Asian (SAS) AF: 0.00 AC: 0 AN: 77514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4026

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1072276

Other (OTH) AF: 0.00 AC: 0 AN: 57112

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.009211), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 1 Pathogenic:9 Other:1

Aug 21, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2020

Department of Paediatrics and Adolescent Medicine, The University of Hong Kong

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jul 17, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013349 /PMID: 12960218 /3billion dataset). 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. -

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GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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/. -

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Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PTPN11 c.5C>T (p.Thr2Ile) variant has been reported in several individuals affected with Noonan syndrome and the variant reportedly occurred de novo in at least two reported individuals (El-Ayadi M et al., PMID: 30693642. Fung JLF et al., PMID: 32963807; Louati R et al., PMID: 25337068; Sarkozy A et al., PMID: 12960218; Thiel C et al., PMID: 19449407; van Trier DC et al., PMID: 25862627). This variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Feb 13, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM2_SUP,PP2 -

Mar 22, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jun 24, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 01, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:2

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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. -

Apr 09, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

LEOPARD syndrome 1 Pathogenic:1

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Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP4+PS2 -

Metachondromatosis Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Pathogenic:1

Feb 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		1.9
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
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.40
gMVP		0.39
Mutation Taster		=14/86	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606990; hg19: chr12-112856920;