VCV000013543.5 - ClinVar

NM_006206.6(PDGFRA):c.2525A>T (p.Asp842Val)

Germline

Classification

no assertion criteria provided. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic (1); Uncertain significance (1)

2 out of 2 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

Clinical impact

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Tier I (Strong) for 2 tumor types

2 out of 2 submissions contributed to this classification

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

Oncogenicity

no assertion criteria provided. Learn more about how ClinVar calculates review status.

Oncogenic

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

NM_006206.6(PDGFRA):c.2525A>T (p.Asp842Val)

Variation ID: 13543 Accession: VCV000013543.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q12 4: 54285926 (GRCh38) [ NCBI UCSC ] 4: 55152093 (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	Sep 19, 2013	Apr 13, 2021	Dec 1, 2006
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	May 9, 2025
Somatic - Oncogenicity	Jun 23, 2024	Jun 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006206.6:c.2525A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006197.1:p.Asp842Val	missense
NM_001347828.2:c.2600A>T	NP_001334757.1:p.Asp867Val	missense
NM_001347829.2:c.2525A>T	NP_001334758.1:p.Asp842Val	missense
NM_001347830.2:c.2564A>T	NP_001334759.1:p.Asp855Val	missense
NC_000004.12:g.54285926A>T
NC_000004.11:g.55152093A>T
NG_009250.1:g.61830A>T
LRG_309:g.61830A>T
	P16234:p.Asp842Val

... more HGVS ... less HGVS

Protein change

D842V, D867V, D855V

Other names

Canonical SPDI

NC_000004.12:54285925:A:T

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.

Links

ClinGen: CA123194 UniProtKB: P16234#VAR_066471 OMIM: 173490.0001 dbSNP: rs121908585 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.
PDGFRA		No evidence available	No evidence available	GRCh38 GRCh37	3914	3952

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.
Gastrointestinal stromal tumor	Pathogenic (1)	no assertion criteria provided	Dec 1, 2006	RCV000014501.9
not provided	Uncertain significance (1)	no assertion criteria provided	-	RCV001355194.2

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.
Pathogenic (Dec 01, 2006) C Contributing to aggregate classification	no assertion criteria provided	GASTROINTESTINAL STROMAL TUMOR, SOMATIC	OMIM Accession: SCV000034752.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 12522257‚ 17087943 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided Comment on evidence: In 8 gastrointestinal stromal tumors (see 175510), Heinrich et al. (2003) identified an asp-to-val mutation at codon 842 (D842V) in exon 18 of the PDGFRA … (more) In 8 gastrointestinal stromal tumors (see 175510), Heinrich et al. (2003) identified an asp-to-val mutation at codon 842 (D842V) in exon 18 of the PDGFRA gene, encoding the activation loop. The mutation was limited to the tumor and was not found in genomic DNA from any of the affected individuals. Using in vitro functional expression studies, De Raedt et al. (2006) demonstrated that the D842V mutation resulted in autophosphorylation and activation of the receptor, as well as IL3 (147740)-independent growth. The D842V mutant protein was not sensitive to imatinib inhibition. (less)

Uncertain significance (-) C Contributing to aggregate classification	no assertion criteria provided	not provided	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001550008.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 4

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12949711, 12522257). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 25230881, 27582545, 28966033, 29763623, 40086436).

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in primary intracranial sarcoma, DICER1-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 12949711). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 30649606, 32291395).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA.	de Raedt T	Gastroenterology	2006	PMID: 17087943
PDGFRA activating mutations in gastrointestinal stromal tumors.	Heinrich MC	Science (New York, N.Y.)	2003	PMID: 12522257

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Gastrointestinal stromal tumor		Oncogenic no assertion criteria provided	-	RCV000014501.9
Primary intracranial sarcoma, DICER1-mutant	Tier I (Strong) - diagnostic - supports diagnosis (1)		Apr 4, 2024	RCV006253552.1
Diffuse midline glioma, H3 K27M-mutant	Tier I (Strong) - diagnostic - supports diagnosis (1)		May 9, 2025	RCV006253551.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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)	Tumor type Help The tumor type 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 Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Tier I (Strong) - Diagnostic - supports diagnosis (May 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Diffuse midline glioma, H3 K27M-mutant	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105503.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (8) PubMed: 12522257‚ 12949711‚ 24705251‚ 25230881‚ 27582545‚ 28966033‚ 29763623‚ 40086436 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12949711, 12522257). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 25230881, 27582545, 28966033, 29763623, 40086436). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Tier I (Strong) - Diagnostic - supports diagnosis (Apr 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Primary intracranial sarcoma, DICER1-mutant	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007104405.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (3) PubMed: 12949711‚ 30649606‚ 32291395 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in primary intracranial sarcoma, DICER1-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 12949711). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 30649606, 32291395). (less) Observation: 1 Collection method: clinical testing Allele origin: somatic Affected status: yes Observation 1 Collection method: clinical testing Allele origin: somatic Affected status: yes

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic (-) C Contributing to aggregate classification	no assertion criteria provided	Gastrointestinal stromal tumor	National Institute of Cancer Research, National Health Research Institutes Accession: SCV005061472.1 First In ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024	Comment: show the literature (less) Observation: 1 Collection method: research Allele origin: somatic Affected status: yes more Observation 1 Collection method: research Allele origin: somatic Affected status: yes Number of individuals with the variant: 2 Family history: no Tissue: GIST tumor Platform type: Sanger sequencing

Comment:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Effective targeting of PDGFRA-altered high-grade glioma with avapritinib.	Mayr L	Cancer cell	2025	PMID: 40086436
DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.	Kamihara J	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc	2020	PMID: 32291395
Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1.	Lee JC	Acta neuropathologica	2019	PMID: 30649606
Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.	Mackay A	Cancer cell	2018	PMID: 29763623
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.	Mackay A	Cancer cell	2017	PMID: 28966033
Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma.	Koschmann C	Oncotarget	2016	PMID: 27582545
Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma.	Jones C	Nature reviews. Cancer	2014	PMID: 25230881
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.	Wu G	Nature genetics	2014	PMID: 24705251
Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors.	Hirota S	Gastroenterology	2003	PMID: 12949711
PDGFRA activating mutations in gastrointestinal stromal tumors.	Heinrich MC	Science (New York, N.Y.)	2003	PMID: 12522257

Text-mined citations for rs121908585 ...

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 Jun 14, 2026