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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:
RCV000617179.11

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]

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 Variant Classification Scheme 2023)		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 providedgermlineunknownnot providednot providednot providednot providednot 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, SCV000740052.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot 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
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 10, 2024