NM_002834.5(PTPN11):c.215C>T (p.Ala72Val) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 22, 2015
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:: RCV000413699.16

Allele description [Variation Report for NM_002834.5(PTPN11):c.215C>T (p.Ala72Val)]

NM_002834.5(PTPN11):c.215C>T (p.Ala72Val)

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.215C>T (p.Ala72Val)

HGVS:

NC_000012.12:g.112450395C>T
NG_007459.1:g.36664C>T
NM_001330437.2:c.215C>T
NM_001374625.1:c.212C>T
NM_002834.5:c.215C>TMANE SELECT
NM_080601.3:c.215C>T
NP_001317366.1:p.Ala72Val
NP_001361554.1:p.Ala71Val
NP_002825.3:p.Ala72Val
NP_542168.1:p.Ala72Val
LRG_614t1:c.215C>T
LRG_614:g.36664C>T
LRG_614p1:p.Ala72Val
NC_000012.11:g.112888199C>T
NM_002834.3:c.215C>T
Q06124:p.Ala72Val

Protein change:

A71V

Links:

UniProtKB: Q06124#VAR_015997; dbSNP: rs121918454

NCBI 1000 Genomes Browser:

rs121918454

Molecular consequence:

NM_001330437.2:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.212C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000491000	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (May 22, 2015)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000491000

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(May 22, 2015)

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	1	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Eurofins Ntd Llc (ga), SCV000058291.9

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

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000491000.2

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

Description

The A72V missense variant in the PTPN11 gene has been reported previously in association with leukemogenesis in Noonan syndrome (Tartaglia et al., 2006; Bocchinfuso et al., 2007). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A72V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same codon (A72S, A72P, A72G) and in nearby residues (Y62N/C, Y63C, E69Q/V, F71I, T73I, E76I/G/A/D/, Q79P/R) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, functional studies of the A72V variant have shown that it results in a conformational shift impairing interactions between the N-SH2 domain and catalytic site while displacing the N-SH2 loop of the protein (Bocchoinfuso et al., 2007).

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058291	Eurofins Ntd Llc (ga)	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (EGL Classification Definitions 2015)	Uncertain significance (Mar 1, 2013)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058291

Eurofins Ntd Llc (ga)

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(EGL Classification Definitions 2015)

Uncertain significance
(Mar 1, 2013)

germline

clinical testing

Citation Link

Last Updated: Nov 10, 2024

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