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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 24, 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:
RCV001852676.6

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]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002235812Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Oct 24, 2022)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD.

Nat Genet. 2001 Dec;29(4):465-8. Erratum in: Nat Genet 2001 Dec;29(4):491. Nat Genet 2002 Jan;30(1):123.

PubMed [citation]
PMID:
11704759

Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.

Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, Kawame H, Kamasaki H, Yamanaka T, Takada F, Nishio K, Sakurai M, Tamai H, Nagashima T, Suzuki Y, Kure S, Fujii K, Imaizumi M, Matsubara Y.

J Hum Genet. 2005;50(4):192-202. doi: 10.1007/s10038-005-0239-7. Epub 2005 Apr 15.

PubMed [citation]
PMID:
15834506
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV002235812.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile282 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 15834506, 19077116, 21407260). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40526). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26817465, 31560489, 34006472). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 282 of the PTPN11 protein (p.Ile282Met).

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

Last Updated: Jul 15, 2024