NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala) AND Noonan syndrome 1

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Sep 1, 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:: RCV000416546.9

Allele description [Variation Report for NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala)]

NM_002834.5(PTPN11):c.179G>C (p.Gly60Ala)

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.179G>C (p.Gly60Ala)

HGVS:

NC_000012.12:g.112450359G>C
NG_007459.1:g.36628G>C
NM_001330437.2:c.179G>C
NM_001374625.1:c.176G>C
NM_002834.5:c.179G>CMANE SELECT
NM_080601.3:c.179G>C
NP_001317366.1:p.Gly60Ala
NP_001361554.1:p.Gly59Ala
NP_002825.3:p.Gly60Ala
NP_002825.3:p.Gly60Ala
NP_542168.1:p.Gly60Ala
LRG_614t1:c.179G>C
LRG_614:g.36628G>C
NC_000012.11:g.112888163G>C
NM_002834.3:c.179G>C
NM_002834.4:c.179G>C
Q06124:p.Gly60Ala
c.179G>C
p.(Gly60Ala)

Protein change:

G59A

Links:

UniProtKB: Q06124#VAR_015602; dbSNP: rs397507509

NCBI 1000 Genomes Browser:

rs397507509

Molecular consequence:

NM_001330437.2:c.179G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.176G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.179G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.179G>C - 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
SCV000494452	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2016)	de novo	clinical testing
SCV000782247	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000992390	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic	de novo	case-control	PubMed (1) [See all records that cite this PMID]
SCV002573168	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29493581, 25741868
SCV002768018	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11992261, 21533187, 24935154, 32164556, 25741868
SCV004100519	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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	1	not provided	not provided	yes	clinical testing, case-control
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.

Gelb BD, Cavé H, Dillon MW, Gripp KW, Lee JA, Mason-Suares H, Rauen KA, Williams B, Zenker M, Vincent LM; ClinGen RASopathy Working Group..

Genet Med. 2018 Nov;20(11):1334-1345. doi: 10.1038/gim.2018.3. Epub 2018 Mar 1.

PubMed [citation]

PMID:: 29493581
PMCID:: PMC6119537

See all PubMed Citations (7)

Details of each submission

From Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV000494452.2

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782247.1

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

From Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, SCV000992390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	case-control	PubMed (1)

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

From 3billion, SCV002573168.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040493 ) and different missense changes at the same codon (p.Gly60Arg, p.Gly60Asp, p.Gly60Cys, p.Gly60Ser, p.Gly60Val/ ClinVar ID: VCV000040490, VCV000041442, VCV000055797, VCV000372590, VCV000987743) have been previously reported as pathogenic/likely pathogenic with strong evidence. 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, SCV002768018.1

#	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 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 21533187, 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 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). (SP) 0701 - Many other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many alternative missense changes have been reported in multiple individuals with Noonan syndrome 1 (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the well reported pathogenic variants causes Noonan syndrome (ClinVar, PMID: 32164556). (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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004100519.3

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

Description

The missense c.179G>Cp.Gly60Ala has been reported in heterozygous state in individuals affected with Noonan syndrome Athota JP, et. al., 2020. Experimental studies indicates that this variant is expected to disrupt PTPN11 function Tartaglia M, et. al.,2002. The p.Gly60Ala variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The amino acid change p.Gly60Ala in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 60 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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