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NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala) AND RASopathy

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jan 11, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000033531.24

Allele description [Variation Report for NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala)]

NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala)

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.1391G>C (p.Gly464Ala)
Other names:
p.G464A:GGC>GCC
HGVS:
  • NC_000012.12:g.112488454G>C
  • NG_007459.1:g.74723G>C
  • NM_001330437.2:c.1403G>C
  • NM_001374625.1:c.1388G>C
  • NM_002834.5:c.1391G>CMANE SELECT
  • NP_001317366.1:p.Gly468Ala
  • NP_001361554.1:p.Gly463Ala
  • NP_002825.3:p.Gly464Ala
  • NP_002825.3:p.Gly464Ala
  • LRG_614t1:c.1391G>C
  • LRG_614:g.74723G>C
  • LRG_614p1:p.Gly464Ala
  • NC_000012.11:g.112926258G>C
  • NM_002834.3:c.1391G>C
  • NM_002834.4:c.1391G>C
Protein change:
G463A; GLY464ALA
Links:
OMIM: 176876.0021; dbSNP: rs121918469
NCBI 1000 Genomes Browser:
rs121918469
Molecular consequence:
  • NM_001330437.2:c.1403G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.1388G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.1391G>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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000549989Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 11, 2024)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV004034108Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 1, 2023)
germlineresearch

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome.

Sarkozy A, Conti E, Digilio MC, Marino B, Morini E, Pacileo G, Wilson M, CalabrĂ² R, Pizzuti A, Dallapiccola B.

J Med Genet. 2004 May;41(5):e68. No abstract available.

PubMed [citation]
PMID:
15121796
PMCID:
PMC1735759

Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome.

Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T, Ogata T.

Am J Med Genet A. 2004 Nov 1;130A(4):432-4. No abstract available.

PubMed [citation]
PMID:
15389709
See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549989.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 464 of the PTPN11 protein (p.Gly464Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with LEOPARD syndrome and Noonan syndrome (PMID: 15121796, 15389709, 16358218, 18678287, 19020799, 25937001). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13343). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 24935154). For these reasons, this variant has been classified as Pathogenic.

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

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV004034108.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024