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NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys) AND RASopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 11, 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:
RCV000556984.7

Allele description [Variation Report for NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys)]

NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys)

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.174C>A (p.Asn58Lys)
Other names:
p.N58K:AAC>AAA
HGVS:
  • NC_000012.12:g.112450354C>A
  • NG_007459.1:g.36623C>A
  • NM_001330437.2:c.174C>A
  • NM_001374625.1:c.171C>A
  • NM_002834.5:c.174C>AMANE SELECT
  • NM_080601.3:c.174C>A
  • NP_001317366.1:p.Asn58Lys
  • NP_001361554.1:p.Asn57Lys
  • NP_002825.3:p.Asn58Lys
  • NP_542168.1:p.Asn58Lys
  • LRG_614t1:c.174C>A
  • LRG_614:g.36623C>A
  • NC_000012.11:g.112888158C>A
  • NM_002834.3:c.174C>A
  • Q06124:p.Asn58Lys
  • c.174C>A
Protein change:
N57K
Links:
UniProtKB: Q06124#VAR_027184; dbSNP: rs397507506
NCBI 1000 Genomes Browser:
rs397507506
Molecular consequence:
  • NM_001330437.2:c.174C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374625.1:c.171C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002834.5:c.174C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_080601.3:c.174C>A - 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
SCV000659040Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 11, 2022) 		germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.

Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M, Ropers HH, Kalscheuer VM.

Eur J Hum Genet. 2003 Feb;11(2):201-6. Erratum in: Eur J Hum Genet. 2003 Jul;11(7):551.

PubMed [citation]
PMID:
12634870

Genotype-phenotype correlations in Noonan syndrome.

Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A.

J Pediatr. 2004 Mar;144(3):368-74.

PubMed [citation]
PMID:
15001945
See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659040.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). 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) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40488). A different variant (c.174C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys).

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

Last Updated: Sep 29, 2024