NM_002834.5(PTPN11):c.417G>T (p.Glu139Asp) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 22, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000033490.15

Allele description [Variation Report for NM_002834.5(PTPN11):c.417G>T (p.Glu139Asp)]

NM_002834.5(PTPN11):c.417G>T (p.Glu139Asp)

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.417G>T (p.Glu139Asp)

Other names:

p.E139D:GAG>GAT

HGVS:

NC_000012.12:g.112453279G>T
NG_007459.1:g.39548G>T
NM_001330437.2:c.417G>T
NM_001374625.1:c.414G>T
NM_002834.5:c.417G>TMANE SELECT
NM_080601.3:c.417G>T
NP_001317366.1:p.Glu139Asp
NP_001361554.1:p.Glu138Asp
NP_002825.3:p.Glu139Asp
NP_542168.1:p.Glu139Asp
LRG_614t1:c.417G>T
LRG_614:g.39548G>T
NC_000012.11:g.112891083G>T
NM_002834.3:c.417G>T
NM_080601.1:c.417G>T
Q06124:p.Glu139Asp
c.417G>T

Protein change:

E138D

Links:

UniProtKB: Q06124#VAR_015613; dbSNP: rs397507520

NCBI 1000 Genomes Browser:

rs397507520

Molecular consequence:

NM_001330437.2:c.417G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.414G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.417G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.417G>T - 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
SCV000549981	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 18372317, 23584145, 20308328, 11992261, 16358218, 19020799, 17339163, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000549981

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 22, 2021)

germline

clinical testing

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

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

Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes.

Martinelli S, Torreri P, Tinti M, Stella L, Bocchinfuso G, Flex E, Grottesi A, Ceccarini M, Palleschi A, Cesareni G, Castagnoli L, Petrucci TC, Gelb BD, Tartaglia M.

Hum Mol Genet. 2008 Jul 1;17(13):2018-29. doi: 10.1093/hmg/ddn099. Epub 2008 Mar 27.

PubMed [citation]

PMID:: 18372317
PMCID:: PMC2900904

Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia.

Müller PJ, Rigbolt KT, Paterok D, Piehler J, Vanselow J, Lasonder E, Andersen JS, Schaper F, Sobota RM.

J Proteomics. 2013 Jun 12;84:132-47. doi: 10.1016/j.jprot.2013.04.005. Epub 2013 Apr 11.

PubMed [citation]

PMID:: 23584145

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549981.8

#	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 glutamic acid with aspartic acid at codon 139 of the PTPN11 protein (p.Glu139Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTPN11 protein function (PMID: 18372317, 23584145, 20308328). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 16358218, 19020799, 17339163). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40512).

#	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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