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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000208002.22

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 with multiple lentigines (NSML)
Synonyms:: Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, Deafness; Cardiomyopathic lentiginosis; LEOPARD syndrome
Identifiers:: MONDO: MONDO:0007893; MedGen: C0175704; Orphanet: 500; OMIM: PS151100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061274	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 12, 2020)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12058348, 16358218, 19133693, 19054014, 19174044, 15520399, 17935252, 18372317, 16377799, 16638574, 18849586, 25741868
SCV000264160	Blueprint Genetics	criteria provided, single submitter (Variant Classification)	Pathogenic (Dec 3, 2015)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22681964, 12058348, 22555271, 22585553, 23813970 Citation Link,
SCV000616375	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Apr 3, 2017)	germline	curation	PubMed (12) [See all records that cite these PMIDs] 15520399, 24935154, 12058348, 20883402, 24767283, 18849586, 29493581, 25884655, 19864201, 16638574, 18372317, 17935252 Citation Link,
SCV000698055	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 21, 2021)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 15385933, 14644997, 16377799, 12058348, 25097206, 19047918, 15001945, 19179468, 17972951, 15710330, 25395418, 24935154, 27276561, 27069254, 32164556, 24775816 Citation Link,
SCV002557046	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21533187, 24935154, 29493581, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	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	clinical testing, curation

Citations

PubMed

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt Iv, Palleschi A, Petrucci TC, Sorcini M, Schoch C, Foa R, Emanuel PD, Gelb BD.

Am J Hum Genet. 2006 Feb;78(2):279-90. Epub 2005 Dec 7.

PubMed [citation]

PMID:: 16358218
PMCID:: PMC1380235

Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade.

Cesarini L, Alfieri P, Pantaleoni F, Vasta I, Cerutti M, Petrangeli V, Mariotti P, Leoni C, Ricci D, Vicari S, Selicorni A, Tartaglia M, Mercuri E, Zampino G.

Am J Med Genet A. 2009 Feb;149A(2):140-6. doi: 10.1002/ajmg.a.32488.

PubMed [citation]

PMID:: 19133693

See all PubMed Citations (36)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061274.7

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

Description

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.

#	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

From Blueprint Genetics, SCV000264160.2

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

#	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 ClinGen RASopathy Variant Curation Expert Panel, SCV000616375.3

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

Description

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.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698055.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

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.

#	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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557046.2

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

Description

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

#	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

Last Updated: Oct 13, 2024

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