NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile) AND Noonan syndrome 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 27, 2023
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:: RCV000014262.37

Allele description [Variation Report for NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile)]

NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile)

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.218C>T (p.Thr73Ile)

Other names:

p.T73I:ACT>ATT

HGVS:

NC_000012.12:g.112450398C>T
NG_007459.1:g.36667C>T
NM_001330437.2:c.218C>T
NM_001374625.1:c.215C>T
NM_002834.5:c.218C>TMANE SELECT
NM_080601.3:c.218C>T
NP_001317366.1:p.Thr73Ile
NP_001361554.1:p.Thr72Ile
NP_002825.3:p.Thr73Ile
NP_542168.1:p.Thr73Ile
LRG_614t1:c.218C>T
LRG_614:g.36667C>T
NC_000012.11:g.112888202C>T
NM_001330437.1:c.218C>T
NM_002834.3:c.218C>T
NM_080601.1:c.218C>T
Q06124:p.Thr73Ile

Protein change:

T72I; THR73ILE

Links:

UniProtKB: Q06124#VAR_015609; OMIM: 176876.0011; dbSNP: rs121918462

NCBI 1000 Genomes Browser:

rs121918462

Molecular consequence:

NM_001330437.2:c.218C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.215C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.218C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.218C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034510	OMIM	no assertion criteria provided	Pathogenic (Apr 15, 2005)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 12161469, 12717436, 15723289
SCV000143816	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	no classification provided	not provided	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV001522576	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002012113	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25097206, 23446178, 20383758, 25741868
SCV004098990	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 27, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26286251, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	unknown	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y, Ogata T.

J Clin Endocrinol Metab. 2002 Aug;87(8):3529-33.

PubMed [citation]

PMID:: 12161469

Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.

Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD, Gelb BD.

Nat Genet. 2003 Jun;34(2):148-50.

PubMed [citation]

PMID:: 12717436

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000034510.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a Japanese patient with sporadic Noonan syndrome (NS1; 163950), Kosaki et al. (2002) identified a 218C-T transition in exon 3 of the PTPN11 gene, resulting in a thr73-to-ile (T73I) substitution.

In 4 children with Noonan syndrome who developed juvenile myelomonocytic leukemia, Tartaglia et al. (2003) observed a heterozygous germline T73I mutation, which alters the N-terminal Src homology 2 (SH2) domain. The T73I mutation was also identified in an individual with growth retardation, pulmonic stenosis, and JMML. Analysis of germline and parental DNAs indicated that the mutations were de novo germline events.

Jongmans et al. (2005) described a patient with Noonan syndrome and mild JMML who carried the T73I mutation.

#	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 Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), SCV000143816.1

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

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

From Baylor Genetics, SCV001522576.2

#	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 3billion, SCV002012113.1

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

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: VCV000013334.14, PMID: 25097206, 23446178, and 20383758, PS2, 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). A different missense change at the same codon (p.Thr73Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044604.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3Cnet: 0.996, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as likely 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	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, SCV004098990.1

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

Description

This heterozygous mis-sense variant is identified in a 3 month male with congenital heart disease, facial dysmorphism, FTT, juvenial myelomonocytic leukemia and echogenic kidney. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.95] predicts deleterious nature of this variant [PP3: Strong]. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 13334] with “conflicting interpretation of pathogenicity, ”Pathogenic (14); Uncertain Significance (1)” interpretation by multiple submitter [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic".

#	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		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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