NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser) AND Noonan syndrome 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 8, 2025
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:: RCV000984919.15

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]

Observations:

Condition(s)

Name:: Noonan syndrome 1 (NS1)
Synonyms:: FEMALE PSEUDO-TURNER SYNDROME; TURNER PHENOTYPE WITH NORMAL KARYOTYPE; PTPN11-Related Noonan Syndrome
Identifiers:: MONDO: MONDO:0008104; MedGen: C4551602; Orphanet: 648; OMIM: 163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000992411	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic	de novo	case-control	PubMed (1) [See all records that cite this PMID]
SCV001132827	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Jan 29, 2019)	germline	clinical testing
SCV005904921	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 19, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15985475, 15001945, 25741868
SCV006554273	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (Hauer et al. (Genet Med. 2018))	Pathogenic (Oct 8, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007096689	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 13, 2025)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24935154, 20301303, 11992261, 21533187, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	2	1	not provided	not provided	yes	case-control
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

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 (9)

Details of each submission

From Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, SCV000992411.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	yes	case-control	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		2	not provided	1	not provided

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001132827.1

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

#	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 3billion, SCV005904921.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.97 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040550 /PMID: 15001945 /3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Pro491Ala, p.Pro491His, p.Pro491Leu, p.Pro491Phe, p.Pro491Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040549, VCV000040551, VCV000040552, VCV000181503 /PMID: 15985475, 17020470, 19621452, 22465605, 28650561 /3billion dataset). 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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV006554273.1

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

Description

This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (III):PP5;PP3;PM5;PM2;PM1;PS2

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV007096689.2

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

Description

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 2 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by mutiple clinical laboratories in ClinVar. - This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from Pro to Ser; This variant is heterozygous; This gene is associated with autosomal dominant disease; Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 3 heterozygote(s), 0 homozygote(s)); Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187; ClinGen expert panel); Variants in this gene are known to have variable expressivity (PMID: 20301303).

#	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: Jun 20, 2026

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