NM_002834.5(PTPN11):c.923A>C (p.Asn308Thr) AND RASopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 15, 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:: RCV001193110.8

Allele description [Variation Report for NM_002834.5(PTPN11):c.923A>C (p.Asn308Thr)]

NM_002834.5(PTPN11):c.923A>C (p.Asn308Thr)

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.923A>C (p.Asn308Thr)

Other names:

p.N308T:AAT>ACT

HGVS:

NC_000012.12:g.112477720A>C
NG_007459.1:g.63989A>C
NM_001330437.2:c.923A>C
NM_001374625.1:c.920A>C
NM_002834.5:c.923A>CMANE SELECT
NM_080601.3:c.923A>C
NP_001317366.1:p.Asn308Thr
NP_001361554.1:p.Asn307Thr
NP_002825.3:p.Asn308Thr
NP_542168.1:p.Asn308Thr
LRG_614t1:c.923A>C
LRG_614:g.63989A>C
NC_000012.11:g.112915524A>C
NM_002834.3:c.923A>C
NM_002834.4:c.923A>C
NM_080601.1:c.923A>C
c.923A>C

Protein change:

N307T

Links:

dbSNP: rs121918455

NCBI 1000 Genomes Browser:

rs121918455

Molecular consequence:

NM_001330437.2:c.923A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.920A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.923A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.923A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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Cd247 protein [Mus musculus]
Cd247 protein [Mus musculus]
gi|31127095|gb|AAH52824.1|

Protein
D16Jhu54 DNA segment, Chr 16, Johns Hopkins University 54 [Mus musculus]
D16Jhu54 DNA segment, Chr 16, Johns Hopkins University 54 [Mus musculus]
Gene ID:93916

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001361726	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 22, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16358218, 18759865, 19077116, 15001945, 28991257, 28921562 Citation Link,
SCV001587259	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11992261, 19077116, 21340158, 28921562, 28991257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001361726

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 22, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV001587259

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2022)

germline

clinical testing

PubMed (6)
[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

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

Tartaglia M, Martinelli S, Stella L, Bocchinfuso G, Flex E, Cordeddu V, Zampino G, Burgt Iv, Palleschi A, Petrucci TC, Sorcini M, Schoch C, Foa R, Emanuel PD, Gelb BD.

Am J Hum Genet. 2006 Feb;78(2):279-90. Epub 2005 Dec 7.

PubMed [citation]

PMID:: 16358218
PMCID:: PMC1380235

PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings.

Lee KA, Williams B, Roza K, Ferguson H, David K, Eddleman K, Stone J, Edelmann L, Richard G, Gelb BD, Kornreich R.

Clin Genet. 2009 Feb;75(2):190-4. doi: 10.1111/j.1399-0004.2008.01085.x. Epub 2008 Aug 26.

PubMed [citation]

PMID:: 18759865

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361726.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: PTPN11 c.923A>C (p.Asn308Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). c.923A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Tartaglia_2006, Lee_2008, Pierpont_2009, Wilbe_2017). These data indicate that the variant is very likely to be associated with disease. In addition, other variants at the same codon have been reported to be associated with Noonan Syndrome, indicating it as a hotspot. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001587259.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn308 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 19077116, 21340158; s16358218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 40535). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 28921562, 28991257). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 308 of the PTPN11 protein (p.Asn308Thr).

#	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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