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NM_002834.5(PTPN11):c.226G>C (p.Glu76Gln) AND RASopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 25, 2022
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:
RCV002281971.1

Allele description [Variation Report for NM_002834.5(PTPN11):c.226G>C (p.Glu76Gln)]

NM_002834.5(PTPN11):c.226G>C (p.Glu76Gln)

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.226G>C (p.Glu76Gln)
Other names:
p.E76Q:GAG>CAG
HGVS:
  • NC_000012.12:g.112450406G>C
  • NG_007459.1:g.36675G>C
  • NM_001330437.2:c.226G>C
  • NM_001374625.1:c.223G>C
  • NM_002834.5:c.226G>CMANE SELECT
  • NM_080601.3:c.226G>C
  • NP_001317366.1:p.Glu76Gln
  • NP_001361554.1:p.Glu75Gln
  • NP_002825.3:p.Glu76Gln
  • NP_542168.1:p.Glu76Gln
  • LRG_614t1:c.226G>C
  • LRG_614:g.36675G>C
  • NC_000012.11:g.112888210G>C
  • NM_002834.3:c.226G>C
  • NM_002834.4:c.226G>C
  • NM_002834.5:c.226G>C
Protein change:
E75Q
Links:
dbSNP: rs121918464
NCBI 1000 Genomes Browser:
rs121918464
Molecular consequence:
  • NM_001330437.2:c.226G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.223G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.226G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080601.3:c.226G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
RASopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: C5555857

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002570731Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jul 25, 2022) 		germlineclinical testing

PubMed (17)
[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

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.

Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Meshinchi S; Children's Cancer Group..

Leukemia. 2004 Nov;18(11):1831-4.

PubMed [citation]
PMID:
15385933

Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.

Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM.

Blood. 2004 Mar 15;103(6):2325-31. Epub 2003 Nov 26.

PubMed [citation]
PMID:
14644997
See all PubMed Citations (17)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570731.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (17)

Description

Variant summary: PTPN11 c.226G>C (p.Glu76Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Other variants at the same codon, p.Glu76Ala, p.Glu76Asp, p.Glu76Gly and p.Glu76Val have been reported in association with Noonan syndrome supporting a mutational hotspot and a critical residue required for protein function. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251068 control chromosomes. c.226G>C has been reported in the literature as a de-novo germline variant in at-least one fetus prenatally affected with Noonan Syndrome (example, Malniece_2020). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant resulted in increased phosphatase activity as compared with wild type, therefore, this alteration is predicted to be activating (LaRochelle_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as 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: Aug 4, 2024