VCV000372590.4 - ClinVar

NM_002834.5(PTPN11):c.178G>C (p.Gly60Arg)

Interpretation:: Pathogenic/Likely pathogenic
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 2
First in ClinVar:: Jan 9, 2017
Most recent Submission:: Jun 22, 2021
Last evaluated:: Jun 7, 2021
Accession:: VCV000372590.4
Variation ID:: 372590
Description:: single nucleotide variant

NM_002834.5(PTPN11):c.178G>C (p.Gly60Arg)

Allele ID

360062

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

12q24.13

Genomic location

12: 112450358 (GRCh38) GRCh38 UCSC

12: 112888162 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.178G>C MANE Select	NP_002825.3:p.Gly60Arg	missense
NM_001330437.2:c.178G>C	NP_001317366.1:p.Gly60Arg	missense
NM_001374625.1:c.175G>C	NP_001361554.1:p.Gly59Arg	missense
NM_080601.3:c.178G>C	NP_542168.1:p.Gly60Arg	missense
NC_000012.12:g.112450358G>C
NC_000012.11:g.112888162G>C
NG_007459.1:g.36627G>C
LRG_614:g.36627G>C
LRG_614t1:c.178G>C

... more HGVS ... less HGVS

Protein change

G60R, G59R

Other names

Canonical SPDI

NC_000012.12:112450357:G:C

Functional consequence

Global minor allele frequency (GMAF)

Allele frequency

Links

ClinGen: CA16042862

dbSNP: rs397507507

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
not provided	Pathogenic	1	criteria provided, single submitter	Mar 6, 2015	RCV000413720.1
RASopathy	Likely pathogenic	1	criteria provided, single submitter	Jun 7, 2021	RCV001201204.2

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
PTPN11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	810	824

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Pathogenic (Mar 06, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490934.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Comment: The G60R variant has been reported previously is association with juvenile myelomonocytic leukemia (Loh et al., 2004). The G60R variant was not observed in approximately … (more) The G60R variant has been reported previously is association with juvenile myelomonocytic leukemia (Loh et al., 2004). The G60R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G60R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at this residue and in nearby residues (N58K, G60S, G60C, G60V, G60A, D61N, Y62N, Y63C) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, G60R is interpreted to be a disease-causing variant (less)
Likely pathogenic (Jun 07, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001372285.2 First in ClinVar: Jul 16, 2020 Last updated: Jun 22, 2021	Publications: PubMed (14) PubMed: 15385933‚ 14644997‚ 15928039‚ 25097206‚ 19047918‚ 19179468‚ 17972951‚ 15710330‚ 25395418‚ 29533785‚ 27276561‚ 27069254‚ 29437595‚ 26457647 Comment: Variant summary: PTPN11 c.178G>C (p.Gly60Arg) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of … (more) Variant summary: PTPN11 c.178G>C (p.Gly60Arg) 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. c.178G>C has been reported in the literature in individuals affected with Juvenile Myelomonocytic Leukemia (JMML) (e.g. Kratz_2005, Loh_2004, Strullu_2014, Streiglitz_2018). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same amino acid residue or nearby residues (e.g. p.N58K, p.G60A, p.G60C, p.G60S, p.D61A, p.D61N) are reported via internal testing and/or in HGMD and ClinVar databases as disease-associated/pathogenic variants for Noonan syndrome, suggesting that this protein region is functionally important. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)

Comment:

The G60R variant has been reported previously is association with juvenile myelomonocytic leukemia (Loh et al., 2004). The G60R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G60R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at this residue and in nearby residues (N58K, G60S, G60C, G60V, G60A, D61N, Y62N, Y63C) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, G60R is interpreted to be a disease-causing variant

Comment:

Variant summary: PTPN11 c.178G>C (p.Gly60Arg) 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. c.178G>C has been reported in the literature in individuals affected with Juvenile Myelomonocytic Leukemia (JMML) (e.g. Kratz_2005, Loh_2004, Strullu_2014, Streiglitz_2018). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same amino acid residue or nearby residues (e.g. p.N58K, p.G60A, p.G60C, p.G60S, p.D61A, p.D61N) are reported via internal testing and/or in HGMD and ClinVar databases as disease-associated/pathogenic variants for Noonan syndrome, suggesting that this protein region is functionally important. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, citing the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Functional evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
Systematic Functional Annotation of Somatic Mutations in Cancer.	Ng PK	Cancer cell	2018	PMID: 29533785
Integrated molecular profiling of juvenile myelomonocytic leukemia.	Murakami N	Blood	2018	PMID: 29437595
Genomic Classification and Prognosis in Acute Myeloid Leukemia.	Papaemmanuil E	The New England journal of medicine	2016	PMID: 27276561
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.	Arber DA	Blood	2016	PMID: 27069254
The genomic landscape of juvenile myelomonocytic leukemia.	Stieglitz E	Nature genetics	2015	PMID: 26457647
Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia.	Stieglitz E	Blood	2015	PMID: 25395418
Juvenile myelomonocytic leukaemia and Noonan syndrome.	Strullu M	Journal of medical genetics	2014	PMID: 25097206
Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis.	Chan G	Blood	2009	PMID: 19179468
Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia.	Yoshida N	Pediatric research	2009	PMID: 19047918
Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD.	Hou HA	Leukemia	2008	PMID: 17972951
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.	Kratz CP	Blood	2005	PMID: 15928039
Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.	Mohi MG	Cancer cell	2005	PMID: 15710330
PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.	Loh ML	Leukemia	2004	PMID: 15385933
Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.	Loh ML	Blood	2004	PMID: 14644997

Text-mined citations for rs397507507...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 11, 2022

ClinVar Genomic variation as it relates to human health

NM_002834.5(PTPN11):c.178G>C (p.Gly60Arg)

NM_002834.5(PTPN11):c.178G>C (p.Gly60Arg)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs397507507...