VCV001463473.12 - ClinVar

NM_002834.5(PTPN11):c.1498C>G (p.Gln500Glu)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (4)

4 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002834.5(PTPN11):c.1498C>G (p.Gln500Glu)

Variation ID: 1463473 Accession: VCV001463473.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.13 12: 112489074 (GRCh38) [ NCBI UCSC ] 12: 112926878 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 28, 2022	Feb 15, 2026	Feb 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.1498C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002825.3:p.Gln500Glu	missense
NM_001330437.2:c.1510C>G	NP_001317366.1:p.Gln504Glu	missense
NM_001374625.1:c.1495C>G	NP_001361554.1:p.Gln499Glu	missense
NM_002834.3:c.1498C>G
NC_000012.12:g.112489074C>G
NC_000012.11:g.112926878C>G
NG_007459.1:g.75343C>G
LRG_614:g.75343C>G

... more HGVS ... less HGVS

Protein change

Q504E, Q500E, Q499E

Other names

Canonical SPDI

NC_000012.12:112489073:C:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA386779820 dbSNP: rs2038714548 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PTPN11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1339	1353

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
RASopathy	Uncertain significance (1)	criteria provided, single submitter	May 7, 2021	RCV001961060.8
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 13, 2023	RCV002224124.2
Juvenile myelomonocytic leukemia LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Feb 27, 2024	RCV002484823.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Nov 20, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002503019.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Secondary finding: no Platform type: NGS

Uncertain significance (Nov 13, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005375879.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29493581, 37445722) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Feb 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV002782332.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (May 07, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	RASopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002239870.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Comment: show 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. 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. This variant has been observed in individual(s) with clinical features of PTPN11-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 500 of the PTPN11 protein (p.Gln500Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29493581, 37445722)

Comment:

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. 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. This variant has been observed in individual(s) with clinical features of PTPN11-related conditions (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 500 of the PTPN11 protein (p.Gln500Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs2038714548 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026