NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Mar 28, 2023
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:: RCV000157678.22

Allele description [Variation Report for NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn)]

NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn)

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.181G>A (p.Asp61Asn)

Other names:

p.D61N:GAT>AAT

HGVS:

NC_000012.12:g.112450361G>A
NG_007459.1:g.36630G>A
NM_001330437.2:c.181G>A
NM_001374625.1:c.178G>A
NM_002834.5:c.181G>AMANE SELECT
NM_080601.3:c.181G>A
NP_001317366.1:p.Asp61Asn
NP_001361554.1:p.Asp60Asn
NP_002825.3:p.Asp61Asn
NP_542168.1:p.Asp61Asn
LRG_614t1:c.181G>A
LRG_614:g.36630G>A
NC_000012.11:g.112888165G>A
NM_001330437.1:c.181G>A
NM_002834.3:c.181G>A
NM_002834.4:c.181G>A
NM_080601.1:c.181G>A
Q06124:p.Asp61Asn

Protein change:

D60N

Links:

UniProtKB: Q06124#VAR_015604; dbSNP: rs397507510

NCBI 1000 Genomes Browser:

rs397507510

Molecular consequence:

NM_001330437.2:c.181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.181G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000057368	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 29, 2022)	germline	clinical testing	Citation Link,
SCV000207649	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	no assertion criteria provided	Pathogenic (Jan 15, 2015)	germline	clinical testing
SCV000886026	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Aug 18, 2017)	germline	clinical testing	Citation Link,
SCV000927554	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Feb 28, 2018)	germline	clinical testing	Citation Link,
SCV001954618	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001973230	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002067410	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002098088	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226874	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 28, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11992261, 15834506, 16358218, 29907801, 35418823, 35885957, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	13	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

Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.

Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, Kawame H, Kamasaki H, Yamanaka T, Takada F, Nishio K, Sakurai M, Tamai H, Nagashima T, Suzuki Y, Kure S, Fujii K, Imaizumi M, Matsubara Y.

J Hum Genet. 2005;50(4):192-202. doi: 10.1007/s10038-005-0239-7. Epub 2005 Apr 15.

PubMed [citation]

PMID:: 15834506

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000057368.17

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

Description

Published functional studies demonstrate the variant results in significantly increased activation of the PTPN11 protein compared to wild type (Niihori et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 32164556, 11992261, 25097206, 26242988, 24803665, 27521173, 26817465, 12634870, 24150203, 28607217, 30417923, 26918529, 30050098, 29907801, 31560489, 30755392, 33300679, 33502061, 32719394, 27535533, 15834506, 9491886, 16053901, 29493581)

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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV000207649.1

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

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000886026.1

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

#	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 Blueprint Genetics, SCV000927554.1

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

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954618.1

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

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001973230.1

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

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

From Genetic Services Laboratory, University of Chicago, SCV002067410.1

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

Description

DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.181G>A, in exon 3 that results in an amino acid change, p.Asp61Asn. This sequence change has not been reported in population databases (gnomAD, ExAC). The p.Asp61Asn change has been identified in several individuals with Noonan syndrome (PMIDs: 11992261, 26242988, 27521173). Other variants at the same amino acid residue (p.Asp61Ala, p.Asp61His, p.Asp61Gly) have also been reported as pathogenic for Noonan syndrome (PMIDs: 19927903, 11704759, 20112233). Functional studies showed that PTPN11 phosphatase activity increased in the presence of this variant (PMID: 15834506). The p.Asp61Asn change affects a highly conserved amino acid residue located in the N-SH2 domain of the PTPN11 protein, which is known to be functional. In-silico pathogenicity prediction tools (PolyPhen2, Align GVGD, REVEL) predict this variant to be deleterious.

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

From Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud, SCV002098088.1

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

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226874.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (7)

Description

PP2, PM1, PM2_supporting, PM5_strong, PS3, PS4

#	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		13	not provided	not provided	not provided

Last Updated: Nov 3, 2024

Relating variation to medicine