NM_002834.5(PTPN11):c.172A>G (p.Asn58Asp) AND Noonan syndrome 1

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jul 24, 2023
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:: RCV001283812.8

Allele description [Variation Report for NM_002834.5(PTPN11):c.172A>G (p.Asn58Asp)]

NM_002834.5(PTPN11):c.172A>G (p.Asn58Asp)

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.172A>G (p.Asn58Asp)

Other names:

p.N58D:AAC>GAC

HGVS:

NC_000012.12:g.112450352A>G
NG_007459.1:g.36621A>G
NM_001330437.2:c.172A>G
NM_001374625.1:c.169A>G
NM_002834.5:c.172A>GMANE SELECT
NM_080601.3:c.172A>G
NP_001317366.1:p.Asn58Asp
NP_001361554.1:p.Asn57Asp
NP_002825.3:p.Asn58Asp
NP_542168.1:p.Asn58Asp
LRG_614t1:c.172A>G
LRG_614:g.36621A>G
NC_000012.11:g.112888156A>G
NM_001330437.1:c.172A>G
NM_002834.3:c.172A>G
NM_002834.4:c.172A>G
c.172A>G

Protein change:

N57D

Links:

dbSNP: rs397507505

NCBI 1000 Genomes Browser:

rs397507505

Molecular consequence:

NM_001330437.2:c.172A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.169A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.172A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.172A>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001469214	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (May 6, 2020)	germline	clinical testing
SCV001736886	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2021)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV002559208	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761828	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12634870, 15001945, 16804314, 25741868
SCV003842014	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29493581, 25741868
SCV004041274	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 24, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.

Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M, Ropers HH, Kalscheuer VM.

Eur J Hum Genet. 2003 Feb;11(2):201-6. Erratum in: Eur J Hum Genet. 2003 Jul;11(7):551.

PubMed [citation]

PMID:: 12634870

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

See all PubMed Citations (5)

Details of each submission

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469214.1

#	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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV001736886.1

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

Description

ACMG codes:PS2; PS4M; PM1; PP2; PP3; PP5

#	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 Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille, SCV002559208.1

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761828.1

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

Description

The PTPN11 c.172A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid asparagine at position 58 in the protein to aspartic acid. This variant has been identified as a de novo variant in this fetus (PS2). The variant has been reported in 8 probands with a clinical presentation of Noonan Syndrome (e.g. PMID: 15001945; PMID: 16804314) (PS4). This variant is absent from population databases (PM2). This variant is a missense change at an amino acid residue where multiple different missense changes have been seen before in association with disease (e.g. PMID: 12634870) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397507505) and in the HGMD database: CM044250. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40487).

#	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, SCV003842014.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. he variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040487). Different missense changes at the same codon (p.Asn58His, p.Asn58Lys, p.Asn58Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040486, VCV000040488, VCV000040489, VCV000181494). 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	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004041274.1

#	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

Last Updated: Nov 3, 2024

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