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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 26, 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:: RCV000033463.20

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]

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
SCV000659041	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 24150203, 27521173, 15834506, 15273746, 16358218, 23321623, 26242988, 28492532
SCV000698039	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 6, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659041

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 26, 2024)

germline

clinical testing

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

SCV000698039

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 6, 2019)

germline

clinical testing

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

Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome.

Rodríguez FA, Unanue N, Hernández MI, Heath KE, Cassorla F.

J Pediatr Endocrinol Metab. 2014 Mar;27(3-4):305-9. doi: 10.1515/jpem-2013-0176.

PubMed [citation]

PMID:: 24150203

Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients.

van Trier DC, Vos AM, Draaijer RW, van der Burgt I, Draaisma JM, Cruysberg JR.

Ophthalmology. 2016 Oct;123(10):2137-46. doi: 10.1016/j.ophtha.2016.06.061. Epub 2016 Aug 9.

PubMed [citation]

PMID:: 27521173

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659041.9

#	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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 61 of the PTPN11 protein (p.Asp61Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15834506, 16358218, 24150203, 26242988, 27521173). ClinVar contains an entry for this variant (Variation ID: 40495). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506). This variant disrupts the p.Asp61 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15273746, 16358218, 23321623, 26242988). 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, SCV000698039.4

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

Description

Variant summary: PTPN11 c.181G>A (p.Asp61Asn) results in a conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252048 control chromosomes. c.181G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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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