NM_002834.5(PTPN11):c.179G>T (p.Gly60Val) AND Noonan syndrome 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 5, 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:: RCV000414941.6

Allele description [Variation Report for NM_002834.5(PTPN11):c.179G>T (p.Gly60Val)]

NM_002834.5(PTPN11):c.179G>T (p.Gly60Val)

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>T (p.Gly60Val)

Other names:

p.G60V

HGVS:

NC_000012.12:g.112450359G>T
NG_007459.1:g.36628G>T
NM_001330437.2:c.179G>T
NM_001374625.1:c.176G>T
NM_002834.5:c.179G>TMANE SELECT
NM_080601.3:c.179G>T
NP_001317366.1:p.Gly60Val
NP_001361554.1:p.Gly59Val
NP_002825.3:p.Gly60Val
NP_542168.1:p.Gly60Val
LRG_614t1:c.179G>T
LRG_614:g.36628G>T
NC_000012.11:g.112888163G>T
NM_002834.3:c.179G>T
NM_080601.1:c.179G>T
Q06124:p.Gly60Val

Protein change:

G59V

Links:

UniProtKB: Q06124#VAR_015990; dbSNP: rs397507509

NCBI 1000 Genomes Browser:

rs397507509

Molecular consequence:

NM_001330437.2:c.179G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.176G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.179G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.179G>T - 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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RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5; Short=BMP synthase CL...
RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5; Short=BMP synthase CLN5; AltName: Full=Ceroid-lipofuscinosis neuronal protein 5; Short=Protein CLN5; AltName: Full=Palmitoyl protein thioesterase CLN5; AltName: Full=S-depalmitoylase CLN5; Contains: RecName: Full=Bis(monoacylglycero)phosphate synthase CLN5, secreted form
gi|187608866|sp|O75503.2|CLN5_HUMAN

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000328729	Baylor Genetics	no assertion criteria provided	Likely pathogenic (Apr 9, 2014)	de novo	clinical testing
SCV001370261	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061169	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 29907801, 18470943, 18701506, 30375388, 22097954, 1672296, 2564168, 2572450, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000328729

Baylor Genetics

no assertion criteria provided

Likely pathogenic
(Apr 9, 2014)

de novo

clinical testing

SCV001370261

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 27, 2019)

unknown

clinical testing

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

SCV002061169

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 5, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

Leach NT, Wilson Mathews DR, Rosenblum LS, Zhou Z, Zhu H, Heim RA.

Genet Med. 2019 Feb;21(2):417-425. doi: 10.1038/s41436-018-0062-0. Epub 2018 Jun 15. Erratum in: Genet Med. 2019 Jul;21(7):1670. doi: 10.1038/s41436-018-0128-z.

PubMed [citation]

PMID:: 29907801

The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders.

Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y.

Hum Mutat. 2008 Aug;29(8):992-1006. doi: 10.1002/humu.20748. Review.

PubMed [citation]

PMID:: 18470943

See all PubMed Citations (9)

Details of each submission

From Baylor Genetics, SCV000328729.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasians	1	not provided	not provided	clinical testing (GTR000508680.4)	not provided

Description

Our laboratory reported dual molecular diagnoses in PTPN11 (NM_002834.3, c.179G>T) and SHH (NM_000193.2, c.1284delC) in one individual with reported features of global developmental delay, hearing loss, hypotonia, hypertonia/spasticity, possible seizures, dysmorphic features (low frontal hairline, frontal bossing, deep set eye, downslanting palpebral fissures, broad based nose, upturned nasal tip), short 5th fingers, macrocephaly, structural brain abnormalities (agenesis of corpus callosum, large post interhemispheric cyst), possible cortical vision impairment, and an atrial septal defect.

#	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	(GTR000508680.4)	1	not provided	1	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001370261.3

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1,PS2,PM1,PP3.

#	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 DASA, SCV002061169.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

The c.179G>T;p.(Gly60Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: ClinVar ID: 55797; PMID: 29907801; 18470943; 18701506) -.PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 30375388) - PMID: 30375388 The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2 domain) - PM1. This variant is not present in population databases (rs397507509 , gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID:40493; 987743; 40490; 372590; 41442) - PM5. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is 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		1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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