NM_002834.5(PTPN11):c.214G>C (p.Ala72Pro) AND Noonan syndrome with multiple lentigines

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 26, 2023
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:: RCV003103718.10

Allele description [Variation Report for NM_002834.5(PTPN11):c.214G>C (p.Ala72Pro)]

NM_002834.5(PTPN11):c.214G>C (p.Ala72Pro)

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.214G>C (p.Ala72Pro)

Other names:

p.A72P:GCC>CCC

HGVS:

NC_000012.12:g.112450394G>C
NG_007459.1:g.36663G>C
NM_001330437.2:c.214G>C
NM_001374625.1:c.211G>C
NM_002834.4:c.214G>C
NM_002834.5:c.214G>CMANE SELECT
NM_080601.3:c.214G>C
NP_001317366.1:p.Ala72Pro
NP_001361554.1:p.Ala71Pro
NP_002825.3:p.Ala72Pro
NP_542168.1:p.Ala72Pro
LRG_614t1:c.214G>C
LRG_614:g.36663G>C
NC_000012.11:g.112888198G>C
NM_002834.3:c.214G>C
NM_080601.1:c.214G>C
c.214G>C

Protein change:

A71P

Links:

dbSNP: rs121918453

NCBI 1000 Genomes Browser:

rs121918453

Molecular consequence:

NM_001330437.2:c.214G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.211G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.214G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.214G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome with multiple lentigines (NSML)
Synonyms:: Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, Deafness; Cardiomyopathic lentiginosis; LEOPARD syndrome
Identifiers:: MONDO: MONDO:0007893; MedGen: C0175704; Orphanet: 500; OMIM: PS151100

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698069	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 26, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 15385933, 14644997, 16358218, 18759865, 19047918, 27259537, 26918529, 19179468, 17972951, 15710330, 25395418, 27069254 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000698069

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 26, 2023)

germline

clinical testing

PubMed (12)
[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

PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.

Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, Cheng JW, Lee CM, Lange BJ, Meshinchi S; Children's Cancer Group..

Leukemia. 2004 Nov;18(11):1831-4.

PubMed [citation]

PMID:: 15385933

Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.

Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH, Cheng JW, Lee CM, Stokoe D, Bonifas JM, Curtiss NP, Gotlib J, Meshinchi S, Le Beau MM, Emanuel PD, Shannon KM.

Blood. 2004 Mar 15;103(6):2325-31. Epub 2003 Nov 26.

PubMed [citation]

PMID:: 14644997

See all PubMed Citations (12)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698069.3

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

Description

Variant summary: PTPN11 c.214G>C (p.Ala72Pro) results in a non-conservative amino acid change located in the N-terminal Src homology 2 (N-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 251056 control chromosomes. c.214G>C has been reported in the literature in individuals affected with Noonan Syndrome (example, PMID: 18759865, 26918529). At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 16358218). The most pronounced variant effect results in statistically significant higher phosphatase activities basally and after stimulation with BTAM peptide consistent with a gain of function mechanism of disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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: Nov 3, 2024

ClinVar

Relating variation to medicine