NM_002834.5(PTPN11):c.178G>A (p.Gly60Ser) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 30, 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:: RCV001219186.9

Allele description [Variation Report for NM_002834.5(PTPN11):c.178G>A (p.Gly60Ser)]

NM_002834.5(PTPN11):c.178G>A (p.Gly60Ser)

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>A (p.Gly60Ser)

Other names:

p.G60S:GGT>AGT

HGVS:

NC_000012.12:g.112450358G>A
NG_007459.1:g.36627G>A
NM_001330437.2:c.178G>A
NM_001374625.1:c.175G>A
NM_002834.5:c.178G>AMANE SELECT
NM_080601.3:c.178G>A
NP_001317366.1:p.Gly60Ser
NP_001361554.1:p.Gly59Ser
NP_002825.3:p.Gly60Ser
NP_542168.1:p.Gly60Ser
LRG_614t1:c.178G>A
LRG_614:g.36627G>A
NC_000012.11:g.112888162G>A
NM_002834.3:c.178G>A
NM_002834.4:c.178G>A
NM_002834.5:c.178G>A

Protein change:

G59S

Links:

dbSNP: rs397507507

NCBI 1000 Genomes Browser:

rs397507507

Molecular consequence:

NM_001330437.2:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.175G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.178G>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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Ralstonia pickettii strain DSM6297 flagellin (fliC) gene, partial cds
Ralstonia pickettii strain DSM6297 flagellin (fliC) gene, partial cds
gi|28974936|gb|AY192717.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001391111	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22465605, 23624134, 11992261, 16643459, 17020470, 24039098, 26817465, 28492532
SCV004804000	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001391111

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 21, 2023)

germline

clinical testing

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

SCV004804000

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 30, 2024)

germline

clinical testing

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

Citation Link

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

IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene.

Bertelloni S, Baroncelli GI, Dati E, Ghione S, Baldinotti F, Toschi B, Simi P.

Hormones (Athens). 2013 Jan-Mar;12(1):86-92.

PubMed [citation]

PMID:: 23624134

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

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001391111.5

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 60 of the PTPN11 protein (p.Gly60Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 22465605, 23624134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40490). 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. 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, 16643459, 17020470, 24039098, 26817465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804000.1

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

Description

Variant summary: PTPN11 c.178G>A (p.Gly60Ser) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250992 control chromosomes (gnomAD). c.178G>A has been reported in the literature as de novo in individuals affected with Noonan Syndrome (example: Ezquieta_2012). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 22465605). ClinVar contains an entry for this variant (Variation ID: 40490). Based on the evidence outlined above, the variant was classified as pathogenic.

#	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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