NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly) AND Noonan syndrome 1

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Dec 20, 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:: RCV000014258.43

Allele description [Variation Report for NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly)]

NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly)

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.182A>G (p.Asp61Gly)

Other names:

p.D61G:GAT>GGT

HGVS:

NC_000012.12:g.112450362A>G
NG_007459.1:g.36631A>G
NM_001330437.2:c.182A>G
NM_001374625.1:c.179A>G
NM_002834.5:c.182A>GMANE SELECT
NM_080601.3:c.182A>G
NP_001317366.1:p.Asp61Gly
NP_001361554.1:p.Asp60Gly
NP_002825.3:p.Asp61Gly
NP_002825.3:p.Asp61Gly
NP_542168.1:p.Asp61Gly
LRG_614t1:c.182A>G
LRG_614:g.36631A>G
LRG_614p1:p.Asp61Gly
NC_000012.11:g.112888166A>G
NM_002834.3:c.182A>G
NM_002834.4:c.182A>G
Q06124:p.Asp61Gly

Protein change:

D60G; ASP61GLY

Links:

UniProtKB: Q06124#VAR_015603; OMIM: 176876.0010; dbSNP: rs121918461

NCBI 1000 Genomes Browser:

rs121918461

Molecular consequence:

NM_001330437.2:c.182A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.179A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.182A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.182A>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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LOC130002128 [Homo sapiens]
LOC130002128 [Homo sapiens]
Gene ID:130002128

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LOC130002109 [Homo sapiens]
LOC130002109 [Homo sapiens]
Gene ID:130002109

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LOC130002148 [Homo sapiens]
LOC130002148 [Homo sapiens]
Gene ID:130002148

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LOC130002123 [Homo sapiens]
LOC130002123 [Homo sapiens]
Gene ID:130002123

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LOC130002143 [Homo sapiens]
LOC130002143 [Homo sapiens]
Gene ID:130002143

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034506	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001482355	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	no assertion criteria provided	Likely pathogenic (May 31, 2019)	maternal	research
SCV001572937	Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 30, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003836330	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 28, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003840155	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	no assertion criteria provided	Pathogenic	unknown	research
SCV004014682	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Dec 20, 2022)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15987685, 15928039, 15273746, 26242988, 11992261, 25097206, 23321623, 26084119 Citation Link,
SCV004190081	Molecular Genetics, Centre for Human Genetics	no assertion criteria provided	Pathogenic	de novo	clinical testing
SCV005382119	Institute of Immunology and Genetics Kaiserslautern	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 8, 2022)	de novo	clinical testing	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	maternal	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	research
not provided	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y, Ogata T.

J Clin Endocrinol Metab. 2002 Aug;87(8):3529-33.

PubMed [citation]

PMID:: 12161469

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 (10)

Details of each submission

From OMIM, SCV000034506.3

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

Description

In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) found an A-to-G transition at nucleotide 182 in exon 3 of the PTPN11 gene, which resulted in an asp61-to-gly (D61G) amino acid substitution.

#	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 Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital, SCV001482355.1

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

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

From Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS, SCV001572937.1

#	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 Baylor Genetics, SCV003836330.1

#	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	unknown	unknown	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, SCV003840155.1

#	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

From Illumina Laboratory Services, Illumina, SCV004014682.1

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

Description

The PTPN11 c.182A>G (p.Asp61Gly) missense variant results in the substitution of asparagine at amino acid position 61 with glycine. This variant is one of the most commonvPTPN11 variants reported in association with Noonan syndrome. Across a selection of the available literature, the c.182A>G variant has been reported in at least 28 individuals with Noonan syndrome, at least six of whom also showed features of juvenile myelomonocytic leukemia or myeloproliferative disorder (PMID: 11992261; PMID: 15928039; PMID: 25097206; PMID: 26084119). The c.182A>G variant has also been shown to occur de novo in at least two additional affected individuals (PMID: 23321623; PMID: 26242988). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Structural modeling has shown that asparagine 61 is located at the N-SH2/PTP interaction surface, which is a mutational hotspot (PMID: 11992261), and functional assays have demonstrated that the variant enhances basal protein activity (gain of function) (PMID: 15987685). A heterozygous knock-in mouse model with the p.Asp61Gly amino acid change exhibits decreased viability and recapitulates clinical features of Noonan syndrome, including short stature, craniofacial anomalies, and myeloproliferative disease (PMID: 15273746). This variant was also identified in a de novo state. Based on the available evidence, the c.182A>G (p.Asp61Gly) variant is classified as pathogenic for Noonan syndrome.

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

From Molecular Genetics, Centre for Human Genetics, SCV004190081.1

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

From Institute of Immunology and Genetics Kaiserslautern, SCV005382119.1

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

Description

ACMG Criteria: PS2, PS3, PM1, PM2_P, PM5, PP2, PP3, PP5; Variant was found heterozygously in de novo-status by prenatal trio exome sequence analysis.

#	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

Last Updated: Nov 3, 2024

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