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NM_002834.5(PTPN11):c.167T>C (p.Ile56Thr) AND Noonan syndrome and Noonan-related syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 10, 2019
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000788007.1

Allele description [Variation Report for NM_002834.5(PTPN11):c.167T>C (p.Ile56Thr)]

NM_002834.5(PTPN11):c.167T>C (p.Ile56Thr)

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.167T>C (p.Ile56Thr)
Other names:
NM_002834.4(PTPN11):c.167T>C
HGVS:
  • NC_000012.12:g.112450347T>C
  • NG_007459.1:g.36616T>C
  • NM_001330437.2:c.167T>C
  • NM_001374625.1:c.164T>C
  • NM_002834.5:c.167T>CMANE SELECT
  • NM_080601.3:c.167T>C
  • NP_001317366.1:p.Ile56Thr
  • NP_001361554.1:p.Ile55Thr
  • NP_002825.3:p.Ile56Thr
  • NP_542168.1:p.Ile56Thr
  • LRG_614t1:c.167T>C
  • LRG_614:g.36616T>C
  • NC_000012.11:g.112888151T>C
  • NC_000012.11:g.112888151T>C
  • NM_002834.3:c.167T>C
Protein change:
I55T
Links:
dbSNP: rs1052382672
NCBI 1000 Genomes Browser:
rs1052382672
Molecular consequence:
  • NM_001330437.2:c.167T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.164T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.167T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080601.3:c.167T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Noonan syndrome and Noonan-related syndrome
Identifiers:
MONDO: MONDO:0020297; MedGen: C5681679; Orphanet: 98733

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000927039ClinGen RASopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)		Likely pathogenic
(May 10, 2019) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927039.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.167T>C (p.Ile56Thr) variant in PTPN11 has been identified in 2 related patients with clinical features of a RASopathy (PS4_Supporting, PP1; Invitae internal data; GTR Lab ID 500031; ClinVar SCV000659038.1). A different pathogenic missense variant (p.Ile56Val) has been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40485). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ile56Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PP1, PM2, PM5, PP2, PP3.

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

Last Updated: Sep 29, 2024