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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 14, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000033466.28

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_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]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000196656	Baylor Genetics	no assertion criteria provided	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000659042	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 9, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11992261, 12325025, 15240615, 16358218, 17020470, 19020799, 19352411, 26817465, 22711529, 28492532
SCV000698065	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 9, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17020470, 16263833, 12960218, 16358218, 11992261, 29907801, 22711529 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001335317	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Feb 14, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 22711529, 26817465, 11992261, 17020470, 12325025, 19352411 Citation Link,
SCV004034101	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2023)	germline	research	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	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, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.

Yoshida R, Hasegawa T, Hasegawa Y, Nagai T, Kinoshita E, Tanaka Y, Kanegane H, Ohyama K, Onishi T, Hanew K, Okuyama T, Horikawa R, Tanaka T, Ogata T.

J Clin Endocrinol Metab. 2004 Jul;89(7):3359-64.

PubMed [citation]

PMID:: 15240615

PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome.

Ko JM, Kim JM, Kim GH, Yoo HW.

J Hum Genet. 2008;53(11-12):999-1006. doi: 10.1007/s10038-008-0343-6. Epub 2008 Nov 20.

PubMed [citation]

PMID:: 19020799

See all PubMed Citations (14)

Details of each submission

From Baylor Genetics, SCV000196656.1

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

Description

Variant classified using ACMG guidelines

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000659042.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 62 of the PTPN11 protein (p.Tyr62Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan-like/multiple giant cell syndrome and Noonan syndrome (PMID: 11992261, 12325025, 15240615, 16358218, 17020470, 19020799, 19352411, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13329). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698065.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: PTPN11 c.184T>G (p.Tyr62Asp) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) 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 251414 control chromosomes (gnomAD). c.184T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Limal_2006, Sarkozy_2003, Tartaglia_2002). These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant resulted in increased PTPN11 activity (Martinelli_2012). Nine ClinVar submitters (evaluation after 2014) cite the variant as 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

From ClinGen RASopathy Variant Curation Expert Panel, SCV001335317.1

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

Description

The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID: 12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID: 22711529). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2.

#	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

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV004034101.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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