NM_002834.5(PTPN11):c.228G>C (p.Glu76Asp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 2, 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:: RCV000033479.10

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Homo sapiens death effector domain containing 2 (DEDD2), transcript variant 9, n...
Homo sapiens death effector domain containing 2 (DEDD2), transcript variant 9, non-coding RNA
gi|1676453065|ref|NR_073051.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000057384	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 18, 2023)	germline	clinical testing	Citation Link,
SCV004563166	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Mar 2, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000057384

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 18, 2023)

germline

clinical testing

Citation Link,

SCV004563166

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Mar 2, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000057384.15

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

Description

Published functional studies demonstrate that the presence of the E76D variant causes increased basal catalytic activity in comparison to wild-type protein (Bocchinfuso et al., 2007); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15987685, 20308328, 24803665, 26607044, 11704759, 28084675, 30417923, 31219622, 31560489, 33318624, 34643321, 17177198, 24077912, 11992261, 9491886, 16053901, 29493581)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563166.1

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

Description

The PTPN11 c.228G>C; p.Glu76Asp variant (rs397507514) is reported in the literature in individuals with Noonan syndrome (Chinton 2019, Li 2019, Tartaglia 2001), and is reported in ClinVar (Variation ID: 40503). Functional analyses show that this variant causes destabilization of the interdomain interface and in vitro phosphatase activity is altered (Bocchinfuso 2007). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.703). Additionally, other variants at this codon (Ala, Gly, Lys and Val) have been reported in individuals with Noonan syndrome or juvenile myelomonocytic leukemia and are considered disease-causing (Tartaglia 2001, Tartaglia 2003). Based on available information, this variant is considered to be pathogenic. References: Bocchinfuso G et al. Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2. Proteins. 2007 Mar 1;66(4):963-74. PMID: 17177198. Chinton J et al. Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. English, Spanish. PMID: 31560489. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759. Tartaglia M et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003 Jun;34(2):148-50. PMID: 12717436.

#	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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