NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 29, 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:: RCV000459297.11

Allele description [Variation Report for NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala)]

NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala)

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.179G>C (p.Gly60Ala)

HGVS:

NC_000012.12:g.112450359G>C
NG_007459.1:g.36628G>C
NM_001330437.2:c.179G>C
NM_001374625.1:c.176G>C
NM_002834.5:c.179G>CMANE SELECT
NM_080601.3:c.179G>C
NP_001317366.1:p.Gly60Ala
NP_001361554.1:p.Gly59Ala
NP_002825.3:p.Gly60Ala
NP_002825.3:p.Gly60Ala
NP_542168.1:p.Gly60Ala
LRG_614t1:c.179G>C
LRG_614:g.36628G>C
NC_000012.11:g.112888163G>C
NM_002834.3:c.179G>C
NM_002834.4:c.179G>C
Q06124:p.Gly60Ala
c.179G>C
p.(Gly60Ala)

Protein change:

G59A

Links:

UniProtKB: Q06124#VAR_015602; dbSNP: rs397507509

NCBI 1000 Genomes Browser:

rs397507509

Molecular consequence:

NM_001330437.2:c.179G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.176G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.179G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.179G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000549986	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 8, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11992261, 16643459, 17020470, 18328949, 24039098, 26817465, 28492532
SCV005185929	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 29, 2024)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 15385933, 14644997, 12717436, 16358218, 17020470, 17546245, 18328949, 11992261, 25097206, 19047918, 19179468, 17972951, 15710330, 25395418, 27276561, 32561839 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000549986

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 8, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV005185929

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 29, 2024)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

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

Acute lymphoblastic leukaemia in Noonan syndrome.

Roti G, La Starza R, Ballanti S, Crescenzi B, Romoli S, Foá R, Tartaglia M, Aversa F, Fabrizio Martelli M, Mecucci C.

Br J Haematol. 2006 May;133(4):448-50. No abstract available.

PubMed [citation]

PMID:: 16643459

Pulmonary interstitial glycogenosis in a patient ultimately diagnosed with Noonan syndrome.

Ross MK, Ellis LS, Bird LM, Hagood JS.

Pediatr Pulmonol. 2014 May;49(5):508-11. doi: 10.1002/ppul.22871. Epub 2013 Sep 3.

PubMed [citation]

PMID:: 24039098

See all PubMed Citations (20)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549986.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 60 of the PTPN11 protein (p.Gly60Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 11992261, 16643459, 17020470, 18328949, 24039098, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40493). 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%. 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, SCV005185929.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: PTPN11 c.179G>C (p.Gly60Ala) 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 251192 control chromosomes (gnomAD). c.179G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2002, 2006, Bertola_2006, Ferfeira_2007, Mutesa_2008). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.178G>A, p.Gly60Ser), supporting the critical relevance of codon 60 to PTPN11 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 15385933, 14644997, 12717436, 16358218, 17020470, 17546245, 18328949, 11992261, 25097206, 19047918, 19179468, 17972951, 15710330, 25395418, 27276561, 27069254, 32561839). ClinVar contains an entry for this variant (Variation ID: 40493). 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: Oct 20, 2024

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