NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp) AND Noonan syndrome 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 2, 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:: RCV000014257.36

Allele description [Variation Report for NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp)]

NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp)

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.184T>G (p.Tyr62Asp)

Other names:

p.Y62D:TAC>GAC

HGVS:

NC_000012.12:g.112450364T>G
NG_007459.1:g.36633T>G
NM_001330437.2:c.184T>G
NM_001374625.1:c.181T>G
NM_002834.5:c.184T>GMANE SELECT
NM_080601.3:c.184T>G
NP_001317366.1:p.Tyr62Asp
NP_001317366.1:p.Tyr62Asp
NP_001361554.1:p.Tyr61Asp
NP_002825.3:p.Tyr62Asp
NP_542168.1:p.Tyr62Asp
LRG_614t1:c.184T>G
LRG_614:g.36633T>G
LRG_614p1:p.Tyr62Asp
NC_000012.11:g.112888168T>G
NM_001330437.1:c.184T>G
NM_002834.3:c.184T>G
NM_002834.4(PTPN11):c.184T>G
NM_002834.4:c.184T>G
Q06124:p.Tyr62Asp

Protein change:

Y61D; TYR62ASP

Links:

UniProtKB: Q06124#VAR_015605; OMIM: 176876.0009; dbSNP: rs121918460

NCBI 1000 Genomes Browser:

rs121918460

Molecular consequence:

NM_001330437.2:c.184T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.181T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.184T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.184T>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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Homo sapiens single stranded DNA binding protein 2 (SSBP2), transcript variant 1...
Homo sapiens single stranded DNA binding protein 2 (SSBP2), transcript variant 12, mRNA
gi|2181862459|ref|NM_001400341.1|

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SRA Links for BioSample (Select 20286382) (1)
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"ISCA Site 6"[submitter] AND "DMD"[gene] (25)
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Cupriavidus DNA gyrase subunit B (gyrB) gene, partial cds.
Cupriavidus DNA gyrase subunit B (gyrB) gene, partial cds.
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txid151654[Organism:noexp] (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034505	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2002)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 12325025, 11992261
SCV000992537	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 10, 2019)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV000999301	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002012325	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26817465, 19352411, 32164556, 31560489, 25533962, 25741868
SCV002768634	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11992261, 21533187, 22711529, 24935154, 25741868

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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	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.

Maheshwari M, Belmont J, Fernbach S, Ho T, Molinari L, Yakub I, Yu F, Combes A, Towbin J, Craigen WJ, Gibbs R.

Hum Mutat. 2002 Oct;20(4):298-304.

PubMed [citation]

PMID:: 12325025

Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations.

Atik T, Aykut A, Hazan F, Onay H, Goksen D, Darcan S, Tukun A, Ozkinay F.

Indian J Pediatr. 2016 Jun;83(6):517-21. doi: 10.1007/s12098-015-1998-6. Epub 2016 Jan 28.

PubMed [citation]

PMID:: 26817465

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000034505.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a subject with Noonan syndrome (NS1; 163950), Maheshwari et al. (2002) found a tyr62-to-asp (Y62D) substitution in exon 3 of the PTPN11 gene. This same mutation was identified by Tartaglia et al. (2002).

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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV000992537.2

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

Description

ACMG codes: PS2, PS3, PM2, PP3, PP5

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

From Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, SCV000999301.1

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

From 3billion, SCV002012325.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000013329.17, PMID: 26817465, 19352411, 32164556, 31560489, 25533962, PS2 and PS4). 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). 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: 0.9, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome 1 (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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768634.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Metachondromatosis (MIM#156250) and Noonan syndrome 1 with or without multiple lentigines (MIM#151100, 163950), respectively (PMID: 21533187, 11992261, 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. Missense variants clustered between N-SH2 and PTP domains have been reported in Noonan syndrome 1 (MIM #163950; PMID: 11992261), except variants in the active site of the PTP domain, which have been reported in Noonan syndrome with multiple lentigines (PMID: 24935154). Null variants have been reported in metachondromatosis individuals (MIM #156250; PMID: 21533187). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 – Multiple alternative amino acid changes at the same position has been observed in gnomAD (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMID: 22711529). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant reported in Noonan syndrome 1 (MIM#163950) and classified as pathogenic by an expert panel in ClinVar (PMID: 22711529 ). (SP) 1208- Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: May 19, 2024

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