NM_002834.5(PTPN11):c.166A>G (p.Ile56Val) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 20, 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:: RCV000557839.11

Allele description [Variation Report for NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)]

NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)

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.166A>G (p.Ile56Val)

Other names:

p.I56V:ATT>GTT; NM_002834.4(PTPN11):c.166A>G

HGVS:

NC_000012.12:g.112450346A>G
NG_007459.1:g.36615A>G
NM_001330437.2:c.166A>G
NM_001374625.1:c.163A>G
NM_002834.5:c.166A>GMANE SELECT
NM_080601.3:c.166A>G
NP_001317366.1:p.Ile56Val
NP_001361554.1:p.Ile55Val
NP_002825.3:p.Ile56Val
NP_002825.3:p.Ile56Val
NP_542168.1:p.Ile56Val
LRG_614t1:c.166A>G
LRG_614:g.36615A>G
NC_000012.11:g.112888150A>G
NM_002834.3:c.166A>G
NM_002834.4:c.166A>G

Protein change:

I55V

Links:

dbSNP: rs397507504

NCBI 1000 Genomes Browser:

rs397507504

Molecular consequence:

NM_001330437.2:c.166A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.163A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.166A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.166A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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Angucyclines and Angucyclinones
Angucyclines and Angucyclinones
Polycyclic aromatic polyketides with tetracyclic angular benz(a)anthracene skeletons. Angucyclines and related angucyclinones are produced by Actinomycetes, e.g., STREPTOMYCES...<br/>Year introduced: 2024

MeSH
Gene neighbors for Gene (Select 5886) (34)
Gene
dbVar for Gene (Select 8175) (280)
dbVar
RecName: Full=UV excision repair protein RAD23 homolog A; Short=HR23A; Short=hHR...
RecName: Full=UV excision repair protein RAD23 homolog A; Short=HR23A; Short=hHR23A
gi|1709983|sp|P54725.1|RD23A_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000659037	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26817465, 28492532
SCV000698061	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 19, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19506109, 26817465, 29907801 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659037

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000698061

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 19, 2019)

germline

clinical testing

PubMed (3)
[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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Dominant-negative ALK2 allele associates with congenital heart defects.

Smith KA, Joziasse IC, Chocron S, van Dinther M, Guryev V, Verhoeven MC, Rehmann H, van der Smagt JJ, Doevendans PA, Cuppen E, Mulder BJ, Ten Dijke P, Bakkers J.

Circulation. 2009 Jun 23;119(24):3062-9. doi: 10.1161/CIRCULATIONAHA.108.843714. Epub 2009 Jun 8.

PubMed [citation]

PMID:: 19506109

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659037.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the PTPN11 protein (p.Ile56Val). 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: 26817465; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40485). 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, SCV000698061.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant Summary: PTPN11 c.166A>G (p.Ile56Val) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 control chromosomes (gnomAD). The variant, c.166A>G, has been reported in the literature and by clinical laboratories in multiple individuals affected with features of Noonan Syndrome and Related Conditions (Smith_2009, Atik_2016, Leach_2018, ClinVar database). Additionally, one reportedly de novo occurrence was observed by a clinical laboratory (ClinVar database). In addition, this variant was identified at our laboratory in one patient with pulmonary stenosis and ASD. These data indicate that the variant is very likely to be associated with disease. Several mutations in neighboring codons (N58K, N58H, and N58D) have been published in association with Noonan Syndrome, emphasizing the functional importance of this residue and/or SH2 region.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as likely pathogenic (3x) and pathogenic (2x). Based on the evidence outlined above, the variant was re-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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