NM_002834.5(PTPN11):c.178G>T (p.Gly60Cys) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 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:: RCV002514147.10

Allele description [Variation Report for NM_002834.5(PTPN11):c.178G>T (p.Gly60Cys)]

NM_002834.5(PTPN11):c.178G>T (p.Gly60Cys)

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.178G>T (p.Gly60Cys)

Other names:

p.G60C:GGT>TGT

HGVS:

NC_000012.12:g.112450358G>T
NG_007459.1:g.36627G>T
NM_001330437.2:c.178G>T
NM_001374625.1:c.175G>T
NM_002834.5:c.178G>TMANE SELECT
NM_080601.3:c.178G>T
NP_001317366.1:p.Gly60Cys
NP_001361554.1:p.Gly59Cys
NP_002825.3:p.Gly60Cys
NP_002825.3:p.Gly60Cys
NP_542168.1:p.Gly60Cys
LRG_614t1:c.178G>T
LRG_614:g.36627G>T
LRG_614p1:p.Gly60Cys
NC_000012.11:g.112888162G>T
NM_002834.3:c.178G>T

Protein change:

G59C

Links:

dbSNP: rs397507507

NCBI 1000 Genomes Browser:

rs397507507

Molecular consequence:

NM_001330437.2:c.178G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.175G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.178G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.178G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003442103	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11992261, 17020470, 18328949, 24039098, 26817465, 16263833, 21407260, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003442103

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 24, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD.

Am J Hum Genet. 2002 Jun;70(6):1555-63. Epub 2002 May 1.

PubMed [citation]

PMID:: 11992261
PMCID:: PMC379142

PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.

Bertola DR, Pereira AC, Albano LM, De Oliveira PS, Kim CA, Krieger JE.

Genet Test. 2006 Fall;10(3):186-91.

PubMed [citation]

PMID:: 17020470

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442103.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly60 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 17020470, 18328949, 24039098, 26817465). 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: 41442). This missense change has been observed in individuals with Noonan syndrome (PMID: 16263833, 21407260). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 60 of the PTPN11 protein (p.Gly60Cys).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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