NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met) AND Noonan syndrome 1

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Mar 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000106323.22

Allele description [Variation Report for NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)]

NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)

Gene:

PTPN11:protein tyrosine phosphatase non-receptor type 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.13

Genomic location:

Preferred name:

NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)

Other names:

p.T468M:ACG>ATG; NM_002834.4(PTPN11):c.1403C>T

HGVS:

NC_000012.12:g.112488466C>T
NG_007459.1:g.74735C>T
NM_001330437.2:c.1415C>T
NM_001374625.1:c.1400C>T
NM_002834.5:c.1403C>TMANE SELECT
NP_001317366.1:p.Thr472Met
NP_001317366.1:p.Thr472Met
NP_001361554.1:p.Thr467Met
NP_002825.3:p.Thr468Met
NP_002825.3:p.Thr468Met
LRG_614t1:c.1403C>T
LRG_614:g.74735C>T
LRG_614p1:p.Thr468Met
NC_000012.11:g.112926270C>T
NM_001330437.1:c.1415C>T
NM_002834.3:c.1403C>T
NM_002834.4:c.1403C>T
c.1403C>T

Protein change:

T467M; THR468MET

Links:

OMIM: 176876.0006; dbSNP: rs121918457

NCBI 1000 Genomes Browser:

rs121918457

Molecular consequence:

NM_001330437.2:c.1415C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.1400C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.1403C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Noonan syndrome 1 (NS1)
Synonyms:: Turner Syndrome, Male; Turner phenotype with normal karyotype; Female pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0008104; MedGen: C4551602; Orphanet: 648; OMIM: 163950

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BioProject
TMTC2 [Colobus angolensis palliatus]
TMTC2 [Colobus angolensis palliatus]
Gene ID:105506099

Gene
Rnf39 ring finger protein 39 [Mus musculus]
Rnf39 ring finger protein 39 [Mus musculus]
Gene ID:386454

Gene
Taxonomy Links for Nucleotide (Select 1935132179) (1)
Taxonomy
PREDICTED: Rattus norvegicus ArfGAP with SH3 domain, ankyrin repeat and PH domai...
PREDICTED: Rattus norvegicus ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (Asap1), transcript variant X9, mRNA
gi|2678957710|ref|XM_063263534.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000143815	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	no classification provided	not provided	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV000494587	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 16, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001164413	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	germline	research	PubMed (6) [See all records that cite these PMIDs] 28681392, 27659786, 27238887, 12058348, 24767283, 25741868
SCV002580322	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841775	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 17935252, 16638574, 18372317, 12058348, 15520399, 20883402, 24935154, 24767283, 25884655, 18849586, 19864201, 25741868
SCV003845204	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32164556, 20493809, 18759865, 25741868
SCV003934965	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 22, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004177104	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004805002	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	2	not provided	literature only
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
Gaucasian	germline	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Noonan syndrome with multiple lentigines with PTPN11 (T468M) gene mutation accompanied with solitary granular cell tumor.

Park SH, Lee SH.

J Dermatol. 2017 Nov;44(11):e280-e281. doi: 10.1111/1346-8138.13960. Epub 2017 Jul 5. No abstract available.

PubMed [citation]

PMID:: 28681392

Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination.

Zhang J, Cheng R, Liang J, Ni C, Li M, Yao Z.

Clin Genet. 2016 Oct;90(4):372-7. doi: 10.1111/cge.12728. Epub 2016 Feb 3.

PubMed [citation]

PMID:: 27659786

See all PubMed Citations (18)

Details of each submission

From Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), SCV000143815.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	2	not provided	not provided		not provided	not provided	not provided	not provided

From Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre, SCV000494587.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Gaucasian	not provided	not provided	not provided	research	PubMed (1)

Description

The patient was diagnosed with typical signs of Noonan syndrome and hypertrophic cardiomyopathy at the age of 2 years old.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164413.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (6)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002580322.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

From 3billion, SCV003841775.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003845204.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam, SCV003934965.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV004177104.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805002.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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