NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser) AND Noonan syndrome 1

Germline classification:: Pathogenic (14 submissions)
Last evaluated:: May 27, 2022
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:: RCV000014255.51

Allele description [Variation Report for NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser)]

NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser)

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.923A>G (p.Asn308Ser)

Other names:

p.N308S:AAT>AGT

HGVS:

NC_000012.12:g.112477720A>G
NG_007459.1:g.63989A>G
NM_001330437.2:c.923A>G
NM_001374625.1:c.920A>G
NM_002834.5:c.923A>GMANE SELECT
NM_080601.3:c.923A>G
NP_001317366.1:p.Asn308Ser
NP_001361554.1:p.Asn307Ser
NP_002825.3:p.Asn308Ser
NP_542168.1:p.Asn308Ser
LRG_614t1:c.923A>G
LRG_614:g.63989A>G
NC_000012.11:g.112915524A>G
NM_001330437.2:c.923A>G
NM_002834.1:c.923A>G
NM_002834.3:c.923A>G
NM_002834.4:c.923A>G
NM_080601.1:c.923A>G
Q06124:p.Asn308Ser
c.923A>G
p.(Asn308Ser)
p.ASN308SER

Protein change:

N307S; ASN308SER

Links:

UniProtKB: Q06124#VAR_015618; OMIM: 176876.0004; dbSNP: rs121918455

NCBI 1000 Genomes Browser:

rs121918455

Molecular consequence:

NM_001330437.2:c.923A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.920A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.923A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.923A>G - 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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D17Jcs64 DNA segment, Chr 17, John C. Schimenti 64 [Mus musculus]
D17Jcs64 DNA segment, Chr 17, John C. Schimenti 64 [Mus musculus]
Gene ID:360054

Gene
LRR receptor-like serine/threonine-protein kinase GHR1 [Benincasa hispida]
LRR receptor-like serine/threonine-protein kinase GHR1 [Benincasa hispida]
gi|1955857769|ref|XP_038886908.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034503	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 11992261, 17497712
SCV000143820	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]
SCV000292239	Center of Genomic medicine, Geneva, University Hospital of Geneva - Final Reports_Cases2015_1	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 4, 2015)	germline	clinical testing
SCV000599278	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 25, 2016)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000782252	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000999380	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001522579	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 7, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001712213	Pediatric Genetics Clinic, Sheba Medical Center	no assertion criteria provided	Pathogenic (May 13, 2021)	de novo	clinical testing
SCV002058627	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002102966	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580188	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761708	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11992261, 15987685, 25741868
SCV002768757	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11992261, 21533187, 24935154, 26817465, 25741868
SCV003840157	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	no assertion criteria provided	Pathogenic	unknown	research

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Summary from all submissions

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

Citations

PubMed

Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations.

Becker K, Hughes H, Howard K, Armstrong M, Roberts D, Lazda EJ, Short JP, Shaw A, Patton MA, Tartaglia M.

Am J Med Genet A. 2007 Jun 1;143A(11):1249-52. No abstract available.

PubMed [citation]

PMID:: 17497712

Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes.

Keilhack H, David FS, McGregor M, Cantley LC, Neel BG.

J Biol Chem. 2005 Sep 2;280(35):30984-93. Epub 2005 Jun 29.

PubMed [citation]

PMID:: 15987685

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000034503.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In affected members of 2 families with Noonan syndrome (NS1; 163950), Tartaglia et al. (2002) identified an 923A-G transition in the PTPN11 gene, resulting in an asn308-to-ser (N308S) substitution. This mutation occurs in the same codon as the common N308D mutation (176876.0003); thus, codon 308 is a hotspot for Noonan syndrome. One of the 2 families in which the N308S mutation was observed had typical features of Noonan syndrome associated with multiple giant cell lesions in bone.

In a case of fetal demise at 12 weeks' gestation, Becker et al. (2007) identified compound heterozygosity for the N308S and Y63C (176876.0008) mutations in the PTPN11 gene. The mother and father, who exhibited facial features of Noonan syndrome and had both undergone surgical correction of pulmonary valve stenosis, were heterozygous for N308S and Y63C, respectively. A second pregnancy resulted in the birth of a boy with Noonan syndrome carrying the paternal Y63C mutation.

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

From Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), SCV000143820.1

#	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	1	not provided	not provided		not provided	not provided	not provided	not provided

From Center of Genomic medicine, Geneva, University Hospital of Geneva - Final Reports_Cases2015_1, SCV000292239.1

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

Description

This variant identified in a very young patient diagnosed with the Noonan syndrome has already been reported to cause this syndrome.

#	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 Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000599278.1

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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782252.1

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

From Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, SCV000999380.1

#	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	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV001522579.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	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 Pediatric Genetics Clinic, Sheba Medical Center, SCV001712213.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV002058627.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013327, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326,VCV000040535, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.685, 3CNET: 0.94, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). 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	1	not provided	not provided		1	not provided	not provided	not provided

From Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine, SCV002102966.1

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

From MGZ Medical Genetics Center, SCV002580188.1

#	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	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002761708.1

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

Description

The PTPN11 c.923A>G variant is classified as a PATHOGENIC variant (PS1, PS3, PS4, PP3) The variant is a single nucleotide change from an adenine to a guanine at position 923 which is predicted to change the Asparagine at position 308 in the protein to Serine. The variant is in exon 8 and is located in protein domains: protein-tyrosine phosphatase (receptor/non-receptor type) of the PTPN11 gene. This variant is a recurrent PTPN11 variant, previously reported in on patient in our laboratory and in multiple individuals with Noonan syndrome across multiple publications, including Tartaglia et al., 2002 (PMID: 11992261) (PS4). This variant is in dbSNP (rs121918455) but is absent from population databases. Other variants at this codon (p.Asn308Asp, p.Asn308Thr) have been previously reported in individuals with Noonan syndrome and are considered pathogenic (PS1). In vitro functional studies have shown that this variant alters substrate specificity and increased catalytic activity relative to the wildtype protein (PMID:15987685) (PS3). The vaviants has been reported in ClinVar (Variation ID: 13327) and HGMD (Accession: CM021135) as pathogenic. Computational predictions support a deleterious effect on the gene or gene product (PP3).

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768757.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - 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). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (PMID: 11992261) within the protein tyrosine phosphatase domain (PMID: 26817465). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative changes, p.(Asn308Asp) and p.(Asn308Thr), have been reported in multiple individuals with Noonan syndrome 1 (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is one of the most commonly reported variants in this gene in individuals with Noonan syndrome 1. (SP) 1102 - Strong phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting 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

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV003840157.1

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

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

Last Updated: Nov 3, 2024

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