NM_002834.5(PTPN11):c.184_185delinsAT (p.Tyr62Ile) AND RASopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003655707.1

Allele description [Variation Report for NM_002834.5(PTPN11):c.184_185delinsAT (p.Tyr62Ile)]

NM_002834.5(PTPN11):c.184_185delinsAT (p.Tyr62Ile)

Gene:

PTPN11:protein tyrosine phosphatase non-receptor type 11 [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

12q24.13

Genomic location:

Preferred name:

NM_002834.5(PTPN11):c.184_185delinsAT (p.Tyr62Ile)

HGVS:

NC_000012.12:g.112450364_112450365delinsAT
NG_007459.1:g.36633_36634delinsAT
NM_001330437.2:c.184_185delinsAT
NM_001374625.1:c.181_182delinsAT
NM_002834.5:c.184_185delinsATMANE SELECT
NM_080601.3:c.184_185delinsAT
NP_001317366.1:p.Tyr62Ile
NP_001361554.1:p.Tyr61Ile
NP_002825.3:p.Tyr62Ile
NP_002825.3:p.Tyr62Ile
NP_542168.1:p.Tyr62Ile
LRG_614t1:c.184_185delTAinsAT
LRG_614:g.36633_36634delinsAT
LRG_614p1:p.Tyr62Ile
NC_000012.11:g.112888168_112888169delinsAT
NM_002834.3:c.184_185delTAinsAT

Protein change:

Y61I

Molecular consequence:

NM_001330437.2:c.184_185delinsAT - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.181_182delinsAT - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.184_185delinsAT - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.184_185delinsAT - 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
SCV004410875	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 17, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11992261, 12325025, 15240615, 16358218, 17020470, 19020799, 19352411, 26817465, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004410875

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 17, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton MA, Gelb BD.

Am J Hum Genet. 2002 Jun;70(6):1555-63. Epub 2002 May 1.

PubMed [citation]

PMID:: 11992261
PMCID:: PMC379142

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

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV004410875.1

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Tyr62 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 12325025, 15240615, 16358218, 17020470, 19020799, 19352411, 26817465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces tyrosine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 62 of the PTPN11 protein (p.Tyr62Ile).

#	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

Last Updated: Feb 28, 2024

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