VCV000597106.48 - ClinVar

NM_002834.5(PTPN11):c.1144G>A (p.Val382Ile)

Germline

Classification

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

Uncertain significance
Uncertain significance (5)

5 out of 5 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.1144G>A (p.Val382Ile)

Variation ID: 597106 Accession: VCV000597106.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.13 12: 112482125 (GRCh38) [ NCBI UCSC ] 12: 112919929 (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	Dec 16, 2018	Jul 27, 2026	Sep 29, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.1144G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002825.3:p.Val382Ile	missense
NM_001330437.2:c.1144G>A	NP_001317366.1:p.Val382Ile	missense
NM_001374625.1:c.1141G>A	NP_001361554.1:p.Val381Ile	missense
NM_080601.3:c.1144G>A	NP_542168.1:p.Val382Ile	missense
NC_000012.12:g.112482125G>A
NC_000012.11:g.112919929G>A
NG_007459.1:g.68394G>A
LRG_614:g.68394G>A
LRG_614t1:c.1144G>A

... more HGVS ... less HGVS

Protein change

V382I, V381I

Other names

Canonical SPDI

NC_000012.12:112482124:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA386775721 dbSNP: rs1214510641 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	1365	1379

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.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2021	RCV000733128.38
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Sep 29, 2025	RCV001868984.7
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Sep 26, 2025	RCV002458349.5
Juvenile myelomonocytic leukemia LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Feb 10, 2022	RCV002499367.2

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 (Feb 10, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia	Fulgent Genetics, Fulgent Genetics Accession: SCV002778219.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (May 10, 2018) C Contributing to aggregate classification	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000861150.2 First in ClinVar: Dec 16, 2018 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: 1 Single Heterozygote Sex: mixed

Uncertain significance (Sep 26, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002616367.4 First in ClinVar: Nov 29, 2022 Last updated: Jan 11, 2026	Publications: PubMed (1) PubMed: 29907801 Comment: show The p.V382I variant (also known as c.1144G>A), located in coding exon 10 of the PTPN11 gene, results from a G to A substitution at nucleotide position 1144. The valine at codon 382 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in a prenatal specimen referred for genetic testing for Noonan syndrome and related disorders; however, details were limited (Leach NT et al. Genet Med, 2019 02;21:417-425). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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

Uncertain significance (Sep 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	RASopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002143718.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Comment: show This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 382 of the PTPN11 protein (p.Val382Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 597106). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTPN11 protein function with a negative predictive value of 80%. 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. (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

Uncertain significance (Dec 01, 2021) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV002063069.33 First in ClinVar: Jan 29, 2022 Last updated: Jul 27, 2026	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

Comment:

The p.V382I variant (also known as c.1144G>A), located in coding exon 10 of the PTPN11 gene, results from a G to A substitution at nucleotide position 1144. The valine at codon 382 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in a prenatal specimen referred for genetic testing for Noonan syndrome and related disorders; however, details were limited (Leach NT et al. Genet Med, 2019 02;21:417-425). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 382 of the PTPN11 protein (p.Val382Ile). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 597106). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTPN11 protein function with a negative predictive value of 80%. 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.	Leach NT	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29907801
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11	-	-	-	-

Text-mined citations for rs1214510641 ...

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 Jul 27, 2026