NM_002834.5(PTPN11):c.228G>C (p.Glu76Asp) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 27, 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:: RCV000472904.10

Allele description [Variation Report for NM_002834.5(PTPN11):c.228G>C (p.Glu76Asp)]

NM_002834.5(PTPN11):c.228G>C (p.Glu76Asp)

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.228G>C (p.Glu76Asp)

Other names:

p.E76D:GAG>GAC

HGVS:

NC_000012.12:g.112450408G>C
NG_007459.1:g.36677G>C
NM_001330437.2:c.228G>C
NM_001374625.1:c.225G>C
NM_002834.5:c.228G>CMANE SELECT
NM_080601.3:c.228G>C
NP_001317366.1:p.Glu76Asp
NP_001361554.1:p.Glu75Asp
NP_002825.3:p.Glu76Asp
NP_542168.1:p.Glu76Asp
LRG_614t1:c.228G>C
LRG_614:g.36677G>C
NC_000012.11:g.112888212G>C
NM_002834.3:c.228G>C
Q06124:p.Glu76Asp
c.228G>C

Protein change:

E75D

Links:

UniProtKB: Q06124#VAR_015610; dbSNP: rs397507514

NCBI 1000 Genomes Browser:

rs397507514

Molecular consequence:

NM_001330437.2:c.228G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.225G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.228G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.228G>C - 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
SCV000549985	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12634870, 16358218, 16830086, 18678287, 19077116, 22190897, 11704759, 15834506, 17177198, 28492532
SCV000920096	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 26, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18470943, 15987685, 20308328 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000549985

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 27, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000920096

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 26, 2017)

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

Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome.

Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M, Ropers HH, Kalscheuer VM.

Eur J Hum Genet. 2003 Feb;11(2):201-6. Erratum in: Eur J Hum Genet. 2003 Jul;11(7):551.

PubMed [citation]

PMID:: 12634870

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt Iv, Palleschi A, Petrucci TC, Sorcini M, Schoch C, Foa R, Emanuel PD, Gelb BD.

Am J Hum Genet. 2006 Feb;78(2):279-90. Epub 2005 Dec 7.

PubMed [citation]

PMID:: 16358218
PMCID:: PMC1380235

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000549985.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16358218, 16830086, 18678287, 19077116, 22190897). ClinVar contains an entry for this variant (Variation ID: 40503). 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. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 11704759, 15834506, 17177198). 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, SCV000920096.1

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

Description

Variant summary: The PTPN11 c.228G>C (p.Glu76Asp) variant involves the alteration of a conserved nucleotide located at the SH2 domain of the protein (InterPro, Keilhack _2005, Edouard_2010). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 215446 control chromosomes (gnomAD). This variant has been reported in many individuals with NS (Tartaglia_2001, Aoki_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies showed variant with mild (2.5-3.1 fold) basal activation compared with WT (Keilhack _2005 and Niihori_2005). A variant involving the same nucleotide, c.228G>T, leading to the same codon change E76D, has been reported in affected individuals and was classified as pathogenic by our lab, suggesting the functional importance of this codon. Taken together, this variant is 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: May 1, 2024

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