NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly) AND RASopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 14, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV002513040.5

Allele description [Variation Report for NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly)]

NM_002834.5(PTPN11):c.227A>G (p.Glu76Gly)

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.227A>G (p.Glu76Gly)

Other names:

p.E76G:GAG>GGG

HGVS:

NC_000012.12:g.112450407A>G
NG_007459.1:g.36676A>G
NM_001330437.2:c.227A>G
NM_001374625.1:c.224A>G
NM_002834.4:c.227A>G
NM_002834.5:c.227A>GMANE SELECT
NM_080601.3:c.227A>G
NP_001317366.1:p.Glu76Gly
NP_001361554.1:p.Glu75Gly
NP_002825.3:p.Glu76Gly
NP_542168.1:p.Glu76Gly
LRG_614t1:c.227A>G
LRG_614:g.36676A>G
NC_000012.11:g.112888211A>G
NM_002834.3:c.227A>G
Q06124:p.Glu76Gly

Protein change:

E75G; GLU76GLY

Links:

UniProtKB: Q06124#VAR_015999; OMIM: 176876.0016; dbSNP: rs121918465

NCBI 1000 Genomes Browser:

rs121918465

Molecular consequence:

NM_001330437.2:c.227A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.224A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.227A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.227A>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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Platelet Storage Pool Deficiency
Platelet Storage Pool Deficiency
Disorder characterized by a decrease or lack of platelet dense bodies in which the releasable pool of adenine nucleotides and 5HT are normally stored.<br/>Year introduced: 1991(1986)

MeSH
Taxonomy Links for Nucleotide (Select 34533663) (1)
Taxonomy
FLNA filamin A [Homo sapiens]
FLNA filamin A [Homo sapiens]
Gene ID:2316

Gene
Gene Links for GEO Profiles (Select 75505747) (1)
Gene
txid2603881[Organism:noexp] (5)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003442104	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 14, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12717436, 14644997, 21901340, 23756559, 23832011, 28098151, 11704759, 12634870, 16830086, 18678287, 22190897, 28492532
SCV003934850	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 22, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 15385933, 14644997, 15834506, 23756559, 25097206, 19047918, 28098151, 19179468, 17972951, 15710330, 25395418, 17942397, 27276561, 27069254, 18559669, 26783207, 32561839, 36349709, 19798502 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003442104

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 14, 2023)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV003934850

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 22, 2023)

germline

clinical testing

PubMed (19)
[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

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD, Gelb BD.

Nat Genet. 2003 Jun;34(2):148-50.

PubMed [citation]

PMID:: 12717436

Gene mutations in the Ras pathway and the prognostic implication in Korean patients with juvenile myelomonocytic leukemia.

Park HD, Lee SH, Sung KW, Koo HH, Jung NG, Cho B, Kim HK, Park IA, Lee KO, Ki CS, Kim SH, Yoo KH, Kim HJ.

Ann Hematol. 2012 Apr;91(4):511-7. doi: 10.1007/s00277-011-1326-9. Epub 2011 Sep 8.

PubMed [citation]

PMID:: 21901340

See all PubMed Citations (28)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442104.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 76 of the PTPN11 protein (p.Glu76Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with somatic juvenile myelomonocytic leukemia and a fetus with a heart defect, hydrops, and persistent cystic hygroma (PMID: 12717436, 14644997, 21901340, 23756559, 23832011, 28098151). ClinVar contains an entry for this variant (Variation ID: 13338). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Glu76 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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, SCV003934850.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

Variant summary: PTPN11 c.227A>G (p.Glu76Gly) results in a non-conservative amino acid change located in the SH2 domain 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 251068 control chromosomes. c.227A>G has been reported in the literature in individuals affected with Noonan Syndrome or Juvenile myelomonocytic leukemia (examples: Unal_2010, Timeus_2013, Mason-Suares_2017). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Ren_2007, Niihori_2005, Lee_2008, Tien_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23756559, 19798502, 36349709, 28098151, 17942397, 15834506, 18559669, 26783207, 19179468). Two ClinVar submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as likely 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: Sep 29, 2024

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