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NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 16, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000617179.10

Allele description [Variation Report for NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)]

NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)

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.417G>C (p.Glu139Asp)
Other names:
p.E139D:GAG>GAC; NM_002834.4(PTPN11):c.417G>C
HGVS:
  • NC_000012.12:g.112453279G>C
  • NG_007459.1:g.39548G>C
  • NM_001330437.2:c.417G>C
  • NM_001374625.1:c.414G>C
  • NM_002834.5:c.417G>CMANE SELECT
  • NM_080601.3:c.417G>C
  • NP_001317366.1:p.Glu139Asp
  • NP_001361554.1:p.Glu138Asp
  • NP_002825.3:p.Glu139Asp
  • NP_002825.3:p.Glu139Asp
  • NP_542168.1:p.Glu139Asp
  • LRG_614t1:c.417G>C
  • LRG_614:g.39548G>C
  • LRG_614p1:p.Glu139Asp
  • NC_000012.11:g.112891083G>C
  • NM_001330437.1:c.417G>C
  • NM_002834.3:c.417G>C
  • NM_002834.4:c.417G>C
  • Q06124:p.Glu139Asp
Protein change:
E138D
Links:
UniProtKB: Q06124#VAR_015613; dbSNP: rs397507520
NCBI 1000 Genomes Browser:
rs397507520
Molecular consequence:
  • NM_001330437.2:c.417G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.414G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.417G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080601.3:c.417G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000740052Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Apr 16, 2021) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder.

Hakami F, Dillon MW, Lebo M, Mason-Suares H.

Prenat Diagn. 2016 May;36(5):418-23. doi: 10.1002/pd.4797. Epub 2016 Mar 28.

PubMed [citation]
PMID:
26918529

Congenital Chylothorax as the Initial Presentation of PTPN11-Associated Noonan Syndrome.

Ebrahimi-Fakhari D, Freiman E, Wojcik MH, Krone K, Casey A, Winn AS, Roberts AE, Harper BD.

J Pediatr. 2017 Jun;185:248-248.e1. doi: 10.1016/j.jpeds.2017.02.042. Epub 2017 Mar 28. No abstract available.

PubMed [citation]
PMID:
28363362
PMCID:
PMC5529256
See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000740052.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)

Description

The p.E139D pathogenic mutation (also known as c.417G>C) is located in coding exon 4 of the PTPN11 gene. This alteration results from a G to C substitution at nucleotide position 417. The glutamic acid at codon 139 is replaced by aspartic acid. This alteration, and another nucleotide change resulting in the same amino acid substitution (c.417G>T), have been detected in multiple individuals reported to have Noonan syndrome or suspected Noonan syndrome, having been reported as occurring de novo in at least one case (Tartaglia M et al. Am J Hum Genet. 2002;70:1555-63; Jongmans M et al. Horm Res. 2004;62 Suppl 3:56-9; Bakker M. Prenat Diagn. 2011;31:833-40; Nair S et al. Pediatr Blood Cancer. 2015;62:1084-6; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337; Athota JP et al. BMC Med Genet, 2020 03;21:50). Some individuals with this alteration were also reported to develop leukemia (JPauli S et al. Am J Med Genet. 2012;158A:652-8; Park HD et al. Ann Hematol. 2012;91:511-7). In addition, this alteration was determined to be the result of de novo mutation or germline mosaicism through whole exome sequencing in 3 families with isolated cases of Noonan syndrome (Ambry internal data). Furthermore, a functional study found this mutation altered the binding specificity of the C-SH2 domain so that they were similar to the N-SH2 domain and increased the phosphopeptide binding affinity (Martinelli S et al. Hum Mol Genet. 2008;17(13):2018-29). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Apr 20, 2024