ClinVar Genomic variation as it relates to human health
NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)
Variation ID: 375682 Accession: VCV000375682.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q32 5: 150125556 (GRCh38) [ NCBI UCSC ] 5: 149505119 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 8, 2017 Jan 7, 2023 May 21, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002609.4:c.1696T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002600.1:p.Trp566Arg missense NM_001355016.2:c.1504T>C NP_001341945.1:p.Trp502Arg missense NM_001355017.2:c.1213T>C NP_001341946.1:p.Trp405Arg missense NC_000005.10:g.150125556A>G NC_000005.9:g.149505119A>G NG_023367.1:g.35304T>C - Protein change
- W566R, W502R, W405R
- Other names
- -
- Canonical SPDI
- NC_000005.10:150125555:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- protein gain of function Variation Ontology [VariO:0040]
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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PDGFRB | - | - |
GRCh38 GRCh37 |
591 | 606 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2016 | RCV000454367.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 21, 2017 | RCV000497546.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2016 | RCV000622279.2 | |
Pathogenic (1) |
no assertion criteria provided
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Feb 18, 2019 | RCV000779640.1 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001257994.1 | |
Pathogenic (2) |
criteria provided, single submitter
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May 21, 2020 | RCV001541889.2 |
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
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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. |
More information
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. |
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Pathogenic
(Jun 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000590605.2
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment:
The W566R variant in the PDGFRB gene has not been reported previously as a germline pathogenic variant nor as a benign variant, to our knowledge. … (more)
The W566R variant in the PDGFRB gene has not been reported previously as a germline pathogenic variant nor as a benign variant, to our knowledge. However, functional studies in tumor cells showed W566R was constitutively activated in contrast to the unstimulated wild-type receptor and was constitutively phosphorylated on tyrosines in NIH3T3 fibroblasts (Arts et al., 2017). The W566R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W566R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W566R as a pathogenic variant (less)
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Pathogenic
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768630.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Loss-of-function: idiopathic basal ganglia calcification (IBGC) syndrome Type 4. Gain-of-Function: infantile myofibromatosis, Penttinen syndrome, and Kosaki overgrowth syndrome (PMID: 31004414) (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to arginine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (juxtamembrane domain (PMID: 30941910). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Minatogawa, M. et al. (2017), PMID: 28639748, 30941910). (P) 1001 - Strong functional evidence supporting abnormal protein function. Functional studies on patient cells indicated that the variant constitutively activates the PI3K-AKT pathway (PMID: 30941910). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Uncertain significance
(Oct 25, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741859.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Thoracolumbar scoliosis (present) , Tall stature (present) , Hyperextensible skin (present) , Pectus excavatum (present) , Scarring (present) , Intellectual disability (present) , Pulmonic stenosis … (more)
Thoracolumbar scoliosis (present) , Tall stature (present) , Hyperextensible skin (present) , Pectus excavatum (present) , Scarring (present) , Intellectual disability (present) , Pulmonic stenosis (disease) (present) , Dandy-Walker syndrome (present) , Muscle weakness (present) , Abnormality of the occipital bone (present) , Abnormality of the frontal bone (present) , Pain (present) , Abnormal nipple morphology (present) , Impaired thermal sensitivity (present) , High palate (present) , Cleft uvula (present) , Increased carrying angle (present) , Broad nail (present) , Long fingers (present) , Long toe (present) , Prominent occiput (present) , Hypertelorism (present) , Malar flattening (present) , Long face (present) , Prominent nasolabial fold (present) , Uplifted earlobe (present) , Posterior scalloping of vertebral bodies (present) , Craniosynostosis (present) , Irregular phalanges (present) , Accelerated skeletal maturation (present) , Hemihypertrophy of lower limb (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
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Pathogenic
(Dec 01, 2016)
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no assertion criteria provided
Method: research, in vitro
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Infantile myofibromatosis
(Somatic mutation)
Affected status: not applicable, yes
Allele origin:
somatic,
not applicable
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Demoulin lab, University of Louvain
Accession: SCV000484407.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
The p.W566R mutation was found in one patient with myofibromatosis. It activates PDGFRB signaling in cell culture (gain of function). We sequenced PDGFRB in myofibromatosis … (more)
The p.W566R mutation was found in one patient with myofibromatosis. It activates PDGFRB signaling in cell culture (gain of function). We sequenced PDGFRB in myofibromatosis cases using the Ion Torrent technology. All variants were confirmed by an alternative method (allele specific PCR or Sanger sequencing). Mutants were functionally characterized in experiments based on cell transfection. In our patient, the p.W566R mutation was associated with a second mutation, c.1998C>A (p.N666K), which also activates the receptor. The two mutations were found in cis (on the same PDGFRB allele). (less)
Observation 1:
Age: 0-9 years
Observation 2:
Comment on evidence:
This mutant constitutively activates receptor signaling in a luciferase assay.
Observation 3:
Comment on evidence:
The transfection of this mutant transforms NIH3T3 fibroblasts and induces the formation of foci, demonstrating that the mutant is oncogenic.
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Pathogenic
(Feb 18, 2019)
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no assertion criteria provided
Method: research
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Infantile myofibromatosis 1
Hydrocephalus
Affected status: yes
Allele origin:
germline
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Dobyns Lab, Seattle Children's Research Institute
Accession: SCV000916317.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Caucasian
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Likely pathogenic
(-)
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no assertion criteria provided
Method: research
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Dandy-Walker malformation
Affected status: yes
Allele origin:
de novo
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University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001434807.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
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Pathogenic
(Jul 20, 2021)
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no assertion criteria provided
Method: literature only
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KOSAKI OVERGROWTH SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001759961.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment on evidence:
In 2 unrelated females with Kosaki overgrowth syndrome (KOGS; 616592), Minatogawa et al. (2017) identified heterozygosity for a c.1696T-C transition (c.1696T-C, NM_002609.3) in exon 12 … (more)
In 2 unrelated females with Kosaki overgrowth syndrome (KOGS; 616592), Minatogawa et al. (2017) identified heterozygosity for a c.1696T-C transition (c.1696T-C, NM_002609.3) in exon 12 of the PDGFRB gene, resulting in a trp566-to-arg (W566R) substitution in the juxtamembrane domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The mutation occurred de novo in patient 1, and was not present in the unaffected mother and sister of patient 2. The variant was not present in the ExAC and gnomAD databases. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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protein gain of function
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Demoulin lab, University of Louvain
Accession: SCV000484407.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Redefining the Etiologic Landscape of Cerebellar Malformations. | Aldinger KA | American journal of human genetics | 2019 | PMID: 31474318 |
A novel de novo PDGFRB variant in a child with severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. | Guimier A | American journal of medical genetics. Part A | 2019 | PMID: 31004414 |
Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome. | Zarate YA | American journal of medical genetics. Part A | 2019 | PMID: 30941910 |
Expansion of the phenotype of Kosaki overgrowth syndrome. | Minatogawa M | American journal of medical genetics. Part A | 2017 | PMID: 28639748 |
PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis. | Arts FA | Human molecular genetics | 2017 | PMID: 28334876 |
Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling. | Arts FA | Journal of cellular and molecular medicine | 2015 | PMID: 25292412 |
Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor. | Irusta PM | The Journal of biological chemistry | 2002 | PMID: 12181311 |
Text-mined citations for rs1060499542 ...
HelpRecord last updated May 27, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.