NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys) AND multiple conditions

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 25, 2022
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:: RCV000515408.12

Allele description [Variation Report for NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)]

NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)

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.188A>G (p.Tyr63Cys)

Other names:

NM_002834.4(PTPN11):c.188A>G; NM_002834.5(PTPN11):c.188A>G

HGVS:

NC_000012.12:g.112450368A>G
NG_007459.1:g.36637A>G
NM_001330437.2:c.188A>G
NM_001374625.1:c.185A>G
NM_002834.5:c.188A>GMANE SELECT
NM_080601.3:c.188A>G
NP_001317366.1:p.Tyr63Cys
NP_001361554.1:p.Tyr62Cys
NP_002825.3:p.Tyr63Cys
NP_002825.3:p.Tyr63Cys
NP_542168.1:p.Tyr63Cys
LRG_614t1:c.188A>G
LRG_614:g.36637A>G
NC_000012.11:g.112888172A>G
NM_001330437.1:c.188A>G
NM_002834.3:c.188A>G
NM_002834.4:c.188A>G
NM_002834.5:c.188A>G
NM_080601.1:c.188A>G
Q06124:p.Tyr63Cys
c.188A>G

Protein change:

Y62C; TYR63CYS

Links:

UniProtKB: Q06124#VAR_015606; OMIM: 176876.0008; dbSNP: rs121918459

NCBI 1000 Genomes Browser:

rs121918459

Molecular consequence:

NM_001330437.2:c.188A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.185A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.188A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.188A>G - missense variant - [Sequence Ontology: SO:0001583]

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

Name:: Juvenile myelomonocytic leukemia (JMML)
Synonyms:: LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
Identifiers:: MONDO: MONDO:0011908; MedGen: C0349639; Orphanet: 86834; OMIM: 607785; Human Phenotype Ontology: HP:0012209

Name:: Metachondromatosis (METCDS)
Identifiers:: MONDO: MONDO:0007979; MedGen: C0410530; Orphanet: 2499; OMIM: 156250

Name:: LEOPARD syndrome 1 (LPRD1)
Synonyms:: LENTIGINOSIS, CARDIOMYOPATHIC; MULTIPLE LENTIGINES SYNDROME
Identifiers:: MONDO: MONDO:0100082; MedGen: C4551484; Orphanet: 500; OMIM: 151100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000611303	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002495907	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000611303

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 18, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002495907

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 25, 2022)

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

Citations

PubMed

Nothing to display

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000611303.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV002495907.2

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

Description

This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, 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: Nov 18, 2024

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