chr12-112488466-C-T

Position:

• chr12-112488466-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PP2 PP3 PM6_Strong PS3 PS4 PP1_Strong PM1

This summary comes from the ClinGen Evidence Repository: The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID:24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220134/MONDO:0007893/004

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:36 O:2
• Conservation: PhyloP100: 7.57

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 20 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1403C>T	p.Thr468Met	missense_variant	12/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1415C>T	p.Thr472Met	missense_variant	12/16
PTPN11	NM_001374625.1	c.1400C>T	p.Thr467Met	missense_variant	12/16
PTPN11	XM_011538613.3	c.1412C>T	p.Thr471Met	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1403C>T	p.Thr468Met	missense_variant	12/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251186 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460722 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726744

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000926 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2022	Published functional studies demonstrate a damaging effect with the T468M variant inducing a weakening of the interaction between the N-SH2 and PTP domains, which leads to a mutant protein that is more readily activated (Yu et al., 2014); 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; This variant is associated with the following publications: (PMID: 26607044, 26377682, 27236105, 25322695, 27484170, 17697839, 26686981, 29493581, 30025578, 28152038, 24803665, 21910245, 23813970, 20493809, 21365175, 16638574, 18372317, 18849586, 20883402, 16377799, 23457302, 22555271, 20308328, 24935154, 22585553, 25884655, 12058348, 24767283, 17935252, 27666661, 26742426, 26337637, 27659786, 26952712, 27238887, 28456002, 19174044, 29346770, 29084544, 16358218, 30762279, 29445579, 19054014, 30417923, 30050098, 31560489, 31722741, 32164556, 29907801, 31370276, 33318624, 33870545, 15520399, 32627323, 33673806, 27535533, 24077912) -

Noonan syndrome 1 Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16638574, 18372317, 18849586, 24935154). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013331). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12058348, 15520399, 17935252, 19864201, 20883402, 24767283, 25884655). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15520399, 17935252, 20883402, 24767283). Different missense changes at the same codon (p.Thr468Glu, p.Thr468Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040547, VCV000265663). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	Jun 22, 2022	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Thr468Met variant in PTPN11 was identified by our study in two unrelated individuals with Noonan syndrome. This variant has been identified in 0.004484% (1/22300) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918457). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rare disease sometimes diagnosed in adulthood. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The PTPN11 gene has a low rate of benign missense variation, raising the possibility that a change in this gene may not be tolerated. This variant has been reported as pathogenic in ClinVar (Variation ID: 13331). The p.Thr468Met variant in PTPN11 has been reported in 12 individuals with Noonan syndrome in the literature (PMID: 28681392, 27659786, 27238887, 12058348, 24767283). In summary, the p.Thr468Met variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PM6_Strong, PP1_Strong, PP2, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Heterozygous Missense variant c.1403C>T in Exon 12 of the PTPN11 gene that results in the amino acid substitution p.Thr468Met was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID : 13331]. The observed variation has previously been reported for Noonan syndrome by Athota, Jeevana Praharsha, et al., 2020. In vitro functional studies and animal models in zebrafish provide some evidence that the p.Thr468Met variant may impact protei n function [Stewart, Rodney A., et al., 2010]. Prenatally, the diagnosis of Noonan syndrome has been suspected following certain ultrasound findings, such as cystic hygroma, increased nuchal translucency (NT) and hydrops fetalis [Lee, K. A., et al., 2009]. For these reasons this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Oct 23, 2023	The PTPN11 c.1403C>T (p.Thr468Met) variant has been reported in several individuals with clinical features of a RASopathy, and is reported to segregate with disease in at least one family (Kato H et al., PMID: 20883402; Keren B et al., PMID: 15520399; Lin IS et al., PMID: 19864201; Santoro C et al., PMID: 24767283; Spatola M et al., PMID: 25884655; Writzl K et al., PMID: 17935252). This variant has been reported in the ClinVar database as a germline pathogenic variant by many submitters, including an expert panel. This variant is only observed on 1/251,186 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a location that has been defined by the ClinGen RASopathy Expert Panel to be a hotspot or functional domain (Gelb BD et al., PMID: 29493581) and computational predictors indicate that the variant is damaging, evidence that correlates with impact to PTPN11 function. In support of this prediction, functional studies show altered protein activity in several different assays (Martinelli S et al., PMID: 18372317; Oishi K et al., PMID: 18849586; Yu ZH et al., PMID: 24935154). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868) and the ClinGen RASopathy Expert Panel recommendations (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Nov 16, 2016	The patient was diagnosed with typical signs of Noonan syndrome and hypertrophic cardiomyopathy at the age of 2 years old. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 09, 2022	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -

Noonan syndrome with multiple lentigines Pathogenic:5

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences as well as more than 5 other independent occurances of patients with clinical features of a RASopathy (PM6_Strong, PS4; PMID 25884655, 19864201, PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399). The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11 (PM1; PMID 29493581). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr468Met variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4, PP1_Strong, PS3, PM1, PP2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene. Loss of function has been associated with protein truncating variants causing metachondromatosis (PMID: 21533187), whereas missense variants have been shown to cause a gain of function effect resulting in Noonan syndrome and Noonan syndrome with multiple lengitines (PMID: 24935154). 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine (exon 12). 0302 - Variant is present in gnomAD >=0.0002 and <0.001 for dominant indication (1 heterozygote, 0 homozygotes). 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. 0602 - Variant affects known hotspot region or cluster of pathogenic variants (tyrosine-protein phosphatase; NCBI, PDB). 0703 - Comparable variant in relevant codon/region has moderate previous evidence for pathogenicity. Two alternative changes resulting in different residues have been reported pathogenic (ClinVar). 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic multiple times (ClinVar) and changes in this residue are the second most common cause of Noonan syndrome with multiple lengitines (PMID: 29493581) 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1205 - Variant is maternally inherited. Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 21, 2021	Variant summary: PTPN11 c.1403C>T (p.Thr468Met) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251186 control chromosomes (gnomAD). c.1403C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (e.g. Digilio_2002, Zenker_2004, Carcavilla_2013, Athota_2020). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to be catalytically defective, affecting SHP2 phosphatase activity and inducing a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to a mutant protein that is more readily activated (e.g. Kontaridis_2006, Yu_2014). Eighteen ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2020	The p.Thr468Met variant in PTPN11 has been reported in >30 probands with clinical features of Noonan syndrome with multiple lentigines (Digilio 2002, Keren 2004, Tartaglia 2006, Cesarini 2009). It has also been shown to segregate with disease in 5 affected relatives (Digilio 2002, Keren 2004, Writzl 2007). It was absent from large population studies. In vitro functional studies and animal models in zebrafish provide some evidence that the p.Thr468Met variant may impact protein function (Stewart 2010). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome with multiple lentigines in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. -

LEOPARD syndrome 1 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Dec 22, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2010	- -
Pathogenic, criteria provided, single submitter	research	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Jun 14, 2016	The patient was diagnosed with classical LEOPARD syndrome with hypertrophic cardiomyopathy. The pathogenic allele is inherited from mother who also has typical signs of LEOPARD syndrome but without hypertrophic cardiomyopathy. -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24935154; 18372317; 16638574; 18849586) - PS3.The c.1403C>T;p.(Thr468Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13331; PMID: PMID 25884655; PMID: 19864201; PMID: 20883402; PMID: 15520399; PMID: 17935252; PMID: 24767283; PMID: 12058348; PMID: 15520399) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Y_phosphatase - PMID 29493581) - PM1. This variant is not present in population databases (rs121918457- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID 25884655; 19864201; PMIDs: 20883402; 15520399; 17935252; 24767283; 12058348; 15520399) - PM6_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24767283, 17935252, 15520399, 20883402) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2016	- -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PTPN11 NM_002834.4 exon 12 p.Thr468Met (c.1403C>T): This variant has been reported in the literature in several individuals with Noonan syndrome with multiple lentigines and other RASopathies; it has been seen both as a de novo variant and as segregating with disease in multiple affected family members (Digilio 2002 PMID:12058348, Keren 2004 PMID:15520399, Writzl 2007 PMID:17935252, Lin 2009 PMID:19864201, Hansen 2009 PMID:19174044, Santoro 2014 PMID:24767284, Spatola 2015 PMID:25884655, Chinton 2019 PMID:31560489, Athota 2020 PMID:32164556). This variant is present in 0.009% (1/10440) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112488466-C-T?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is also present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13331). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Hanna 2006 PMID:16638574, Kontaridis 2006 PMID:16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586, Yu 2013 PMID:23457302). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 468 of the PTPN11 protein (p.Thr468Met). This variant is present in population databases (rs121918457, gnomAD 0.004%). This missense change has been observed in individuals with LEOPARD syndrome and other Noonan spectrum disorders (PMID: 12058348, 21910245, 22555271, 22585553, 23813970, 24767283). ClinVar contains an entry for this variant (Variation ID: 13331). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 16638574, 18372317, 20535210, 23457302, 24935154). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -

PTPN11-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Jul 05, 2018

- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jul 28, 2017

The PTPN11 Thr468Met variant has been reported in over 50 probands affected with LEOPARD syndrome and other Noonan spectrum disorders, including at least 4 de novo events and has been found to segregate in multiple families (see literature). We identified PTPN11 Thr468Met in a proband of Southern Eastern European descent who was diagnosed with atypical HCM. Sanger sequencing did not identify this variant in either the proband's mother or father, hence the variant has occurred de novo in our proband. The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF= 0.000008; http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster and PolyPhen2 predict this variant to be deleterious. Functional studies suggest that the variant results in reduced catalytic function (see literature). In summary, based on identification of the variant in multiple affected probands, the occurence of affected de novo individuals, functional studies displaying an affect on the protein function, segregation of the variant in affected family members, in silico tools in support of a deleterious affect and because missense variants in PTPN11 are a known mechanism of disease in Rasopathies, we classify PTPN11 Thr468Met as "pathogenic". -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The p.T468M pathogenic mutation (also known as c.1403C>T), located in coding exon 12 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1403. The threonine at codon 468 is replaced by methionine, an amino acid with similar properties. This alteration has been well described in association with LEOPARD syndrome (also known as Noonan syndrome with multiple lentigines), and has shown segregation among several families (Digilio MC et al. Am. J. Hum. Genet., 2002 Aug;71:389-94; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90; Carcavilla A et al. Eur. J. Pediatr., 2011 Aug;170:1069-74; Kindel SJ et al. J. Card. Fail., 2012 May;18:396-403). One family described included individuals with hypertrophic cardiomyopathy and overlapping clinical features of neurofibromatosis and LEOPARD syndrome (Carcavilla A et al. Eur. J. Pediatr., 2011 Aug;170:1069-74). Medulloblastoma has been reported in one individual with this mutation (Rankin J et al. Am. J. Med. Genet. A, 2013 Aug;161A:2027-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, functional analyses demonstrated that the p.T468M alteration resulted in loss of normal tyrosine phosphatase activity (Hanna N et al. FEBS Lett., 2006 May;580:2477-82; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	.;H;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.92		Loss of catalytic residue at T468 (P = 0.0132);.;.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.96

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: rs121918457; hg19: chr12-112926270; COSMIC: COSV61005439; COSMIC: COSV61005439;