NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys) AND Noonan syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 25, 2024
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:: RCV000577894.19

Allele description [Variation Report for NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)]

NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)

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.836A>G (p.Tyr279Cys)

Other names:

p.Y279C:TAT>TGT

HGVS:

NC_000012.12:g.112473023A>G
NG_007459.1:g.59292A>G
NM_001330437.2:c.836A>G
NM_001374625.1:c.833A>G
NM_002834.5:c.836A>GMANE SELECT
NM_080601.3:c.836A>G
NP_001317366.1:p.Tyr279Cys
NP_001361554.1:p.Tyr278Cys
NP_002825.3:p.Tyr279Cys
NP_002825.3:p.Tyr279Cys
NP_542168.1:p.Tyr279Cys
LRG_614t1:c.836A>G
LRG_614:g.59292A>G
LRG_614p1:p.Tyr279Cys
NC_000012.11:g.112910827A>G
NM_001330437.1:c.836A>G
NM_002834.3:c.836A>G
NM_002834.4:c.836A>G
NM_080601.1:c.836A>G
NM_080601.2:c.836A>G
Q06124:p.Tyr279Cys
p.Tyr279His

Protein change:

Y278C; TYR279CYS

Links:

UniProtKB: Q06124#VAR_015614; OMIM: 176876.0005; dbSNP: rs121918456

NCBI 1000 Genomes Browser:

rs121918456

Molecular consequence:

NM_001330437.2:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.833A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.836A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Noonan syndrome 1 (NS1)
Synonyms:: Turner Syndrome, Male; Turner phenotype with normal karyotype; Female pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0008104; MedGen: C4551602; Orphanet: 648; OMIM: 163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000583577	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (White et al. (Am J Hum Genet. 2018))	Likely pathogenic (Jun 1, 2017)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000680351	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Dec 18, 2017)	de novo	clinical testing	Citation Link,
SCV000854622	Baylor Genetics	no assertion criteria provided	Pathogenic (Nov 18, 2018)	germline	clinical testing
SCV002011980	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24820750, 25917897, 25741868
SCV004805927	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

White JJ, Mazzeu JF, Coban-Akdemir Z, Bayram Y, Bahrambeigi V, Hoischen A, van Bon BWM, Gezdirici A, Gulec EY, Ramond F, Touraine R, Thevenon J, Shinawi M, Beaver E, Heeley J, Hoover-Fong J, Durmaz CD, Karabulut HG, Marzioglu-Ozdemir E, Cayir A, Duz MB, Seven M, et al.

Am J Hum Genet. 2018 Jan 4;102(1):27-43. doi: 10.1016/j.ajhg.2017.10.002. Epub 2017 Dec 21.

PubMed [citation]

PMID:: 29276006
PMCID:: PMC5777383

Leopard syndrome caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene in a sporadic case of Chinese Han.

Wang Y, Chen C, Wang DW.

Int J Cardiol. 2014 Jul 1;174(3):e101-4. doi: 10.1016/j.ijcard.2014.04.161. Epub 2014 Apr 22. No abstract available.

PubMed [citation]

PMID:: 24820750

See all PubMed Citations (4)

Details of each submission

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000583577.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680351.1

#	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	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided

From Baylor Genetics, SCV000854622.1

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

From 3billion, SCV002011980.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID:VCV000013328.26, PS1). The variant has been observed in at least two similarly affected unrelated individuals (3billion dataset, PS4_M). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Tyr279Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000065666.4, PMID: 24820750 and 25917897, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.973, 3Cnet: 0.607, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805927.1

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

#	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 16, 2024

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