NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser) AND RASopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 23, 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:: RCV000033536.21

Allele description [Variation Report for NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser)]

NM_002834.5(PTPN11):c.1471C>T (p.Pro491Ser)

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.1471C>T (p.Pro491Ser)

Other names:

p.P491S:CCC>TCC

HGVS:

NC_000012.12:g.112489047C>T
NG_007459.1:g.75316C>T
NM_001330437.2:c.1483C>T
NM_001374625.1:c.1468C>T
NM_002834.5:c.1471C>TMANE SELECT
NP_001317366.1:p.Pro495Ser
NP_001317366.1:p.Pro495Ser
NP_001361554.1:p.Pro490Ser
NP_002825.3:p.Pro491Ser
NP_002825.3:p.Pro491Ser
LRG_614t1:c.1471C>T
LRG_614:g.75316C>T
NC_000012.11:g.112926851C>T
NM_001330437.1:c.1483C>T
NM_002834.3:c.1471C>T
NM_002834.4:c.1471C>T
c.1471C>T

Protein change:

P490S

Links:

dbSNP: rs397507539

NCBI 1000 Genomes Browser:

rs397507539

Molecular consequence:

NM_001330437.2:c.1483C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.1468C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.1471C>T - 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
SCV000196652	Baylor Genetics	no assertion criteria provided	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000549982	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 23, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15985475, 19621452, 16358218, 17020470, 19077116, 22465605, 28492532
SCV000920099	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 18, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12717436, 14982869, 16358218, 17020470, 18080325, 19077116, 15985475, 18470943, 26607044 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000196652

Baylor Genetics

no assertion criteria provided

Pathogenic

unknown

clinical testing

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

SCV000549982

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 23, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000920099

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 18, 2019)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Genotype-phenotype correlations in Noonan syndrome.

Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H, Reis A, Rauch A.

J Pediatr. 2004 Mar;144(3):368-74.

PubMed [citation]

PMID:: 15001945

Pilocytic astrocytoma in a child with Noonan syndrome.

Schuettpelz LG, McDonald S, Whitesell K, Desruisseau DM, Grange DK, Gurnett CA, Wilson DB.

Pediatr Blood Cancer. 2009 Dec;53(6):1147-9. doi: 10.1002/pbc.22193.

PubMed [citation]

PMID:: 19621452

See all PubMed Citations (13)

Details of each submission

From Baylor Genetics, SCV000196652.1

#	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, SCV000549982.6

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 19621452, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 40550). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 16358218, 17020470, 19077116, 22465605). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs397507539, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 491 of the PTPN11 protein (p.Pro491Ser).

#	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, SCV000920099.2

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

Description

Variant summary: Variant summary: PTPN11 c.1471C>T (p.Pro491Ser) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain and Tyrosine specific protein phosphatases domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found in 1/246860 control chromosomes, a frequency of 4.1e-06. c.1471C>T has been reported in the literature in numerous individuals affected with Noonan Syndrome or related disorders, indicating the variant is very likely to be associated with disease. In addition, several variants causing a change at the same codon have been reported as associated with Noonan Syndrome (p.P491A, p.P491H, p.P491L, p.P491T), suggesting the proline is critical for proper gene function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified 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

Last Updated: Oct 13, 2024

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