NM_002834.5(PTPN11):c.172A>C (p.Asn58His) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 9, 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:: RCV000456871.9

Allele description [Variation Report for NM_002834.5(PTPN11):c.172A>C (p.Asn58His)]

NM_002834.5(PTPN11):c.172A>C (p.Asn58His)

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.172A>C (p.Asn58His)

Other names:

p.N58H:AAC>CAC

HGVS:

NC_000012.12:g.112450352A>C
NG_007459.1:g.36621A>C
NM_001330437.2:c.172A>C
NM_001374625.1:c.169A>C
NM_002834.5:c.172A>CMANE SELECT
NM_080601.3:c.172A>C
NP_001317366.1:p.Asn58His
NP_001361554.1:p.Asn57His
NP_002825.3:p.Asn58His
NP_542168.1:p.Asn58His
LRG_614t1:c.172A>C
LRG_614:g.36621A>C
NC_000012.11:g.112888156A>C
NM_002834.3:c.172A>C
NM_002834.4:c.172A>C
c.172A>C

Protein change:

N57H

Links:

dbSNP: rs397507505

NCBI 1000 Genomes Browser:

rs397507505

Molecular consequence:

NM_001330437.2:c.172A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.169A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.172A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.172A>C - 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
SCV000549997	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 9, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15001945, 15956085, 19125092, 16263833, 16358218, 21204800, 23624134, 23756559, 28492532
SCV001774647	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 19, 2021)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 15385933, 14644997, 16358218, 16263833, 25097206, 19047918, 24803665, 26918529, 19179468, 17972951, 15710330, 25395418, 23624134, 27276561, 27069254, 31219622, 30417923 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000549997

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 9, 2022)

germline

clinical testing

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

SCV001774647

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 19, 2021)

germline

clinical testing

PubMed (17)
[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	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

PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome.

Ferreira LV, Souza SA, Arnhold IJ, Mendonca BB, Jorge AA.

J Clin Endocrinol Metab. 2005 Sep;90(9):5156-60. Epub 2005 Jun 14.

PubMed [citation]

PMID:: 15956085

See all PubMed Citations (23)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000549997.6

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15001945, 15956085, 19125092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40486). This missense change has been observed in individuals with Noonan syndrome (PMID: 16263833, 16358218, 21204800, 23624134, 23756559). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58His).

#	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, SCV001774647.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

Variant summary: PTPN11 c.172A>C (p.Asn58His) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251000 control chromosomes (gnomAD). c.172A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2005, Limal_2006, Bertelloni_2013, Hakami_2016, Bessis_2019, Li_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants at the same codon (N58D, N58K, N58I) have been classified as pathogenic by our laboratory indicating the asparagine residue is critical for the protein function. Six ClinVar submitters (evaluation after 2014) cite 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: Sep 29, 2024

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