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NM_002834.5(PTPN11):c.846C>G (p.Ile282Met) AND Noonan syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Dec 21, 2018
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:
RCV000037661.10

Allele description [Variation Report for NM_002834.5(PTPN11):c.846C>G (p.Ile282Met)]

NM_002834.5(PTPN11):c.846C>G (p.Ile282Met)

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.846C>G (p.Ile282Met)
Other names:
p.I282M:ATC>ATG
HGVS:
  • NC_000012.12:g.112473033C>G
  • NG_007459.1:g.59302C>G
  • NM_001330437.2:c.846C>G
  • NM_001374625.1:c.843C>G
  • NM_002834.5:c.846C>GMANE SELECT
  • NM_080601.3:c.846C>G
  • NP_001317366.1:p.Ile282Met
  • NP_001317366.1:p.Ile282Met
  • NP_001361554.1:p.Ile281Met
  • NP_002825.3:p.Ile282Met
  • NP_542168.1:p.Ile282Met
  • LRG_614t1:c.846C>G
  • LRG_614:g.59302C>G
  • NC_000012.11:g.112910837C>G
  • NM_001330437.1:c.846C>G
  • NM_002834.3:c.846C>G
  • NM_002834.4:c.846C>G
  • c.846C>G
Protein change:
I281M
Links:
dbSNP: rs397507530
NCBI 1000 Genomes Browser:
rs397507530
Molecular consequence:
  • NM_001330437.2:c.846C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.843C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.846C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080601.3:c.846C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061323Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Likely pathogenic
(Dec 21, 2018)
germlineclinical testing

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

SCV001438413Service de Génétique Moléculaire, Hôpital Robert Debré
no assertion criteria provided
Likely pathogenicde novoclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided32not providednot providednot providedclinical testing
not providedde novoyesnot provided2not providednot providednot providedclinical testing

Citations

PubMed

The integrated landscape of driver genomic alterations in glioblastoma.

Frattini V, Trifonov V, Chan JM, Castano A, Lia M, Abate F, Keir ST, Ji AX, Zoppoli P, Niola F, Danussi C, Dolgalev I, Porrati P, Pellegatta S, Heguy A, Gupta G, Pisapia DJ, Canoll P, Bruce JN, McLendon RE, Yan H, Aldape K, et al.

Nat Genet. 2013 Oct;45(10):1141-9. doi: 10.1038/ng.2734. Epub 2013 Aug 5.

PubMed [citation]
PMID:
23917401
PMCID:
PMC3799953

Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations.

Atik T, Aykut A, Hazan F, Onay H, Goksen D, Darcan S, Tukun A, Ozkinay F.

Indian J Pediatr. 2016 Jun;83(6):517-21. doi: 10.1007/s12098-015-1998-6. Epub 2016 Jan 28.

PubMed [citation]
PMID:
26817465
See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061323.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (3)

Description

The p.Ile282Met variant in PTPN11 has been reported in 3 individuals with clinic al features of Noonan syndrome and was inherited from an affected parent in one of these cases (Atik 2016, Klapecki 2005, LMM unpublished data). This variant wa s absent from large population studies. It has been reported in ClinVar (Variat ion ID 40526) and has been reported as a somatic variant in a glioblastoma (Frat tini 2013). Computational prediction tools and conservation analysis suggest th at this variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. Furthermore, another variant at this positi on (p.Ile282Val) has been reported in multiple individuals with clinical feature s of Noonan syndrome and is classified as pathogenic by our laboratory and in Cl inVar (Variation ID 40525). In summary, although additional studies are required to fully establish its clinical significance, the p.Ile282Met variant is likely pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: P M2, PM5, PP3, PS4_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not provided2not provided

From Service de Génétique Moléculaire, Hôpital Robert Debré, SCV001438413.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot provided2not provided

Last Updated: Jul 15, 2024