NM_002834.5(PTPN11):c.172A>C (p.Asn58His) AND Noonan syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 25, 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:: RCV000037626.8

Allele description [Variation Report for NM_002834.5(PTPN11):c.172A>C (p.Asn58His)]

NM_002834.5(PTPN11):c.172A>C (p.Asn58His)

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>C (p.Asn58His)

Other names:

p.N58H:AAC>CAC

HGVS:

NC_000012.12:g.112450352A>C
NG_007459.1:g.36621A>C
NM_001330437.2:c.172A>C
NM_001374625.1:c.169A>C
NM_002834.5:c.172A>CMANE SELECT
NM_080601.3:c.172A>C
NP_001317366.1:p.Asn58His
NP_001361554.1:p.Asn57His
NP_002825.3:p.Asn58His
NP_542168.1:p.Asn58His
LRG_614t1:c.172A>C
LRG_614:g.36621A>C
NC_000012.11:g.112888156A>C
NM_002834.3:c.172A>C
NM_002834.4:c.172A>C
c.172A>C

Protein change:

N57H

Links:

dbSNP: rs397507505

NCBI 1000 Genomes Browser:

rs397507505

Molecular consequence:

NM_001330437.2:c.172A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.169A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.172A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.172A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome; Pseudo-Turner 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
SCV000061288	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Oct 23, 2015)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 15001945, 12634870, 16358218, 16263833, 22465605, 22190897, 25914815, 24150203, 19125092, 21407260, 23624134, 23832011, 24033266
SCV000805099	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Pathogenic (Jun 7, 2016)	germline	clinical testing
SCV002318975	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22465605, 33128510, 16263833, 16358218, 23624134, 26918529, 15001945, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061288

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Oct 23, 2015)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV000805099

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

no assertion criteria provided

Pathogenic
(Jun 7, 2016)

germline

clinical testing

SCV002318975

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 25, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	4	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

RASopathies: Clinical Diagnosis in the First Year of Life.

Digilio MC, Lepri F, Baban A, Dentici ML, Versacci P, Capolino R, Ferese R, De Luca A, Tartaglia M, Marino B, Dallapiccola B.

Mol Syndromol. 2011 Sep;1(6):282-289. Epub 2011 Sep 14.

PubMed [citation]

PMID:: 22190897
PMCID:: PMC3214957

See all PubMed Citations (16)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061288.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (13)

Description

The p.Asn58His variant in PTPN11 has been previously identified in at least 8 in dividuals with clinical features of Noonan syndrome or Cardio-facio-cutaneous sy ndrome, including two reportedly de novo occurrences (Tartaglia 2006, Limal 2006 , Ezquieta 2012, Bertelloni 2013, LMM unpublished data). It was absent from larg e population studies. In addition, two different amino acid changes at this posi tion (Asn58Asp, Asn58Lys) has also been reported in individuals with clinical fe atures of Noonan syndrome (Mustante 2003, Zenker 2004, Tartaglia 2006, Sherman 2 009, Digilio 2011, Coromilas 2015). Computational prediction tools and conservat ion analysis suggest that this variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, this var iant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner (http://pcpgmwww.partners.org/personalizedmedicince/L MM) based upon segregation studies and absence from controls.

#	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		5	not provided	4	not provided

From Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000805099.1

#	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 DASA, SCV002318975.1

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

Description

The c.172A>C;p.(Asn58His) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 40486; PMID:22465605; PMID:33128510; PMID:16263833; PMID:16358218; PMID:23624134; PMID:26918529)- PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2 domain; PMID: 20301303) - PM1. Pathogenic missense variant in this residue have been reported (Clinvar ID: 40487; PMID: 26918529; 15001945; 22465605) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 22465605) - PM6. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic

#	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

Last Updated: Sep 29, 2024

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