NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys) AND RASopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 4, 2020
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:: RCV000033476.14

Allele description [Variation Report for NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys)]

NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys)

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.226G>A (p.Glu76Lys)

Other names:

p.E76K:GAG>AAG

HGVS:

NC_000012.12:g.112450406G>A
NG_007459.1:g.36675G>A
NM_001330437.2:c.226G>A
NM_001374625.1:c.223G>A
NM_002834.4:c.226G>A
NM_002834.5:c.226G>AMANE SELECT
NM_080601.3:c.226G>A
NP_001317366.1:p.Glu76Lys
NP_001317366.1:p.Glu76Lys
NP_001361554.1:p.Glu75Lys
NP_002825.3:p.Glu76Lys
NP_542168.1:p.Glu76Lys
LRG_614t1:c.226G>A
LRG_614:g.36675G>A
NC_000012.11:g.112888210G>A
NM_001330437.1:c.226G>A
NM_002834.3:c.226G>A
Q06124:p.Glu76Lys

Protein change:

E75K; GLU76LYS

Links:

UniProtKB: Q06124#VAR_016000; OMIM: 176876.0014; dbSNP: rs121918464

NCBI 1000 Genomes Browser:

rs121918464

Molecular consequence:

NM_001330437.2:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.223G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.226G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.226G>A - 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
SCV000196661	Baylor Genetics	no assertion criteria provided	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001535902	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 4, 2020)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16830086, 11704759, 18678287, 12634870, 14974085, 19509418, 14644997, 14982869, 12717436, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000196661

Baylor Genetics

no assertion criteria provided

Pathogenic

unknown

clinical testing

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

SCV001535902

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 4, 2020)

germline

clinical testing

PubMed (10)
[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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aortic root dilatation is a rare complication of Noonan syndrome.

Power PD, Lewin MB, Hannibal MC, Glass IA.

Pediatr Cardiol. 2006 Jul-Aug;27(4):478-80. Epub 2006 Jul 6.

PubMed [citation]

PMID:: 16830086

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, van der Burgt I, Crosby AH, Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati RS, Gelb BD.

Nat Genet. 2001 Dec;29(4):465-8. Erratum in: Nat Genet 2001 Dec;29(4):491. Nat Genet 2002 Jan;30(1):123.

PubMed [citation]

PMID:: 11704759

See all PubMed Citations (10)

Details of each submission

From Baylor Genetics, SCV000196661.1

#	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, SCV001535902.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

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.Glu76 amino acid residue in PTPN11. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16830086, 11704759, 18678287, 12634870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect PTPN11 protein function (PMID: 14974085, 19509418). This variant has been observed as a somatic variant in many individuals with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia or JMML; however, it has not been reported as a germline variant in affected individuals (PMID:14644997, 14982869, 12717436). ClinVar contains an entry for this variant (Variation ID: 13336). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 76 of the PTPN11 protein (p.Glu76Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine.

#	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: Nov 3, 2024

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