NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg) AND RASopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 25, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000206837.8

Allele description [Variation Report for NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg)]

NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg)

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.209A>G (p.Lys70Arg)

HGVS:

NC_000012.12:g.112450389A>G
NG_007459.1:g.36658A>G
NM_001330437.2:c.209A>G
NM_001374625.1:c.206A>G
NM_002834.5:c.209A>GMANE SELECT
NM_080601.3:c.209A>G
NP_001317366.1:p.Lys70Arg
NP_001361554.1:p.Lys69Arg
NP_002825.3:p.Lys70Arg
NP_542168.1:p.Lys70Arg
LRG_614t1:c.209A>G
LRG_614:g.36658A>G
NC_000012.11:g.112888193A>G
NM_002834.3:c.209A>G
NM_002834.4:c.209A>G
NM_002834.5(PTPN11):c.209A>GMANE SELECT
c.209A>G

Protein change:

K69R

Links:

dbSNP: rs397516801

NCBI 1000 Genomes Browser:

rs397516801

Molecular consequence:

NM_001330437.2:c.209A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.206A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.209A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.209A>G - 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
SCV000261103	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 29, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29084544, 28492532
SCV001424748	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Jun 25, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001426844	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 8, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29084544, 29907801 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000261103

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 29, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001424748

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Jun 25, 2020)

germline

curation

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

Citation Link,

SCV001426844

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 8, 2020)

germline

clinical testing

PubMed (2)
[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, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders.

Xu S, Fan Y, Sun Y, Wang L, Gu X, Yu Y.

BMC Med Genomics. 2017 Oct 30;10(1):62. doi: 10.1186/s12920-017-0298-6.

PubMed [citation]

PMID:: 29084544
PMCID:: PMC5663114

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000261103.7

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

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. ClinVar contains an entry for this variant (Variation ID: 44603). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 29084544). 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 lysine, which is basic and polar, with arginine, which is basic and polar, at codon 70 of the PTPN11 protein (p.Lys70Arg). For these reasons, this variant has been 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 ClinGen RASopathy Variant Curation Expert Panel, SCV001424748.1

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

Description

The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID: 29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID: 29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Finally, PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6, PM1, PM2, PP1, PP2.

#	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, SCV001426844.1

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

Description

Variant summary: PTPN11 c.209A>G (p.Lys70Arg) 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 251054 control chromosomes (gnomAD). c.209A>G has been reported in the literature in individuals affected with and/or undergoing diagnostic evaluation for Noonan Syndrome And Related Conditions (e.g. Leach_2019, Xu_2017). At least one case of a confirmed de novo occurrence in an individual with Noonan syndrome has been reported (Xu_2017). In addition, a ClinVar submitter reports the variant in at least 5 individuals with clinical features of a RASopathy, including segregation with disease in 3 affected relatives (SCV000061296.6). 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. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2)/likely pathogenic (n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Recently the ClinGen RASopathy Variant Curation Expert Panel settled on a classification of Pathogenic for this variant (personal communication, June 2020). Based on the evidence outlined above, the variant was re-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: Feb 28, 2024

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