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NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys) AND Noonan syndrome with multiple lentigines

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 22, 2019
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:
RCV000030620.10

Allele description [Variation Report for NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)]

NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)

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.836A>G (p.Tyr279Cys)
Other names:
p.Y279C:TAT>TGT
HGVS:
  • NC_000012.12:g.112473023A>G
  • NG_007459.1:g.59292A>G
  • NM_001330437.2:c.836A>G
  • NM_001374625.1:c.833A>G
  • NM_002834.5:c.836A>GMANE SELECT
  • NM_080601.3:c.836A>G
  • NP_001317366.1:p.Tyr279Cys
  • NP_001361554.1:p.Tyr278Cys
  • NP_002825.3:p.Tyr279Cys
  • NP_002825.3:p.Tyr279Cys
  • NP_542168.1:p.Tyr279Cys
  • LRG_614t1:c.836A>G
  • LRG_614:g.59292A>G
  • LRG_614p1:p.Tyr279Cys
  • NC_000012.11:g.112910827A>G
  • NM_001330437.1:c.836A>G
  • NM_002834.3:c.836A>G
  • NM_002834.4:c.836A>G
  • NM_080601.1:c.836A>G
  • NM_080601.2:c.836A>G
  • Q06124:p.Tyr279Cys
  • p.Tyr279His
Protein change:
Y278C; TYR279CYS
Links:
UniProtKB: Q06124#VAR_015614; OMIM: 176876.0005; dbSNP: rs121918456
NCBI 1000 Genomes Browser:
rs121918456
Molecular consequence:
  • NM_001330437.2:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080601.3:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Noonan syndrome with multiple lentigines (NSML)
Synonyms:
Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, Deafness; Cardiomyopathic lentiginosis; LEOPARD syndrome
Identifiers:
MONDO: MONDO:0007893; MedGen: C0175704; Orphanet: 500; OMIM: PS151100

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000053298Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Apr 22, 2019) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience.

Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé H; French Collaborative Noonan Study Group..

J Med Genet. 2004 Nov;41(11):e117. No abstract available.

PubMed [citation]
PMID:
15520399
PMCID:
PMC1735627

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
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000053298.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: PTPN11 c.836A>G (p.Tyr279Cys) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245584 control chromosomes (gnomAD). c.836A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (Keren_2004, Harakmi_2016). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies have indicated the variant abolishes enzymatic activity of PTPN11 and increases AKT, the variant's mechanism causes a gain of function (Yu_2014). The variant has been established to be a common disease variant by multiple publications. In addition, nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024