NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser) AND Noonan syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 2, 2020
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:: RCV000157010.23

Allele description [Variation Report for NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser)]

NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser)

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.1471C>T (p.Pro491Ser)

Other names:

p.P491S:CCC>TCC

HGVS:

NC_000012.12:g.112489047C>T
NG_007459.1:g.75316C>T
NM_001330437.2:c.1483C>T
NM_001374625.1:c.1468C>T
NM_002834.5:c.1471C>TMANE SELECT
NP_001317366.1:p.Pro495Ser
NP_001317366.1:p.Pro495Ser
NP_001361554.1:p.Pro490Ser
NP_002825.3:p.Pro491Ser
NP_002825.3:p.Pro491Ser
LRG_614t1:c.1471C>T
LRG_614:g.75316C>T
NC_000012.11:g.112926851C>T
NM_001330437.1:c.1483C>T
NM_002834.3:c.1471C>T
NM_002834.4:c.1471C>T
c.1471C>T

Protein change:

P490S

Links:

dbSNP: rs397507539

Molecular consequence:

NM_001330437.2:c.1483C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.1468C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.1471C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome
Identifiers:: MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061277	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2020)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15001945, 15985475, 14982869, 16358218, 17020470, 30541462, 24891296, 25741868
SCV001156694	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jun 26, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061277

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2020)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001156694

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Jun 26, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genotype-phenotype correlations in Noonan syndrome.

Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A.

J Pediatr. 2004 Mar;144(3):368-74.

PubMed [citation]

PMID:: 15001945

PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome.

Binder G, Neuer K, Ranke MB, Wittekindt NE.

J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Epub 2005 Jun 28.

PubMed [citation]

PMID:: 15985475

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061277.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Pro491Ser variant in PTPN11 has been identified in more than 10 individuals with clinical features of Noonan syndrome, including one individual in whom it occurred de novo (Bertola 2006 PMID: 17020470; Tartaglia 2006 PMID: 16358218; Yang 2018 PMID: 30541462; LMM data). This variant has also been identified as a somatic change occurring in an individual with acute lymphoblastic leukemia (Tartaglia 2004 PMID: 14982869). It has been identified in 0.001% (1/113754) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID 40550). Additionally, several other pathogenic changes (p.Pro491Thr; p.Pro491Leu; p.Pro491His) have been identified at this position, suggesting that this residue is critical to the function of the protein. In vitro functional studies support an impact on protein function (Edwards 2014 PMID: 24891296). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP codes applied: PS4, PM5_Strong, PM6, PS3_Supporting.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156694.2

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

Description

The PTPN11 c.1471C>T; p.Pro491Ser variant (rs397507539) is reported in the literature in multiple individuals affected with Noonan syndrome (Aoki 2008, Rasmussen 2008, Tartaglia 2006, van Trier 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40550). The proline at codon 491 is highly conserved, and functional assays suggest this variant causes increased phosphatase activity of the PTPN11 protein (Edwards 2014). Additionally, other amino acid substitutions at this codon (p.Pro491His, p.Pro491Leu, p.Pro491Phe) have been reported in individuals with Noonan syndrome and are considered disease-causing (Aoki 2008, Binder 2005, Schuettpelz 2009, Tartaglia 2006). Based on available information, the p.Pro491Ser variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Edwards JJ et al. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. Rasmussen KJ et al. Bile duct anomalies in a male child with Noonan syndrome: a case for ras and notch pathway synergism. Am J Med Genet A. 2008 Jan 15;146A(2):261-3. Schuettpelz LG et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer. 2009 Dec;53(6):1147-9. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. van Trier DC et al. Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients. Ophthalmology. 2016 Oct;123(10):2137-46.

#	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: Jun 20, 2026

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