This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP4.
ClinVar Genomic variation as it relates to human health
NM_002609.4(PDGFRB):c.1681C>T (p.Arg561Cys)
Germline
Classification
Help
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.
(9)
Help
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002609.4(PDGFRB):c.1681C>T (p.Arg561Cys)
Variation ID: 55848 Accession: VCV000055848.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q32 5: 150125571 (GRCh38) [ NCBI UCSC ] 5: 149505134 (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 Jul 24, 2013 Feb 28, 2024 Mar 29, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002609.4:c.1681C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002600.1:p.Arg561Cys missense NM_001355016.2:c.1489C>T NP_001341945.1:p.Arg497Cys missense NM_001355017.2:c.1198C>T NP_001341946.1:p.Arg400Cys missense NC_000005.10:g.150125571G>A NC_000005.9:g.149505134G>A NG_023367.1:g.35289C>T P09619:p.Arg561Cys - Protein change
- R561C, R497C, R400C
- Other names
-
NM_002609.3(PDGFRB):c.1681C>T(p.Arg561Cys)
- Canonical SPDI
- NC_000005.10:150125570:G:A
-
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]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| PDGFRB | - | - |
GRCh38 GRCh37 |
624 | 639 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 31, 2018 | RCV000049264.30 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 1, 2016 | RCV000454370.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2023 | RCV000390507.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 29, 2023 | RCV001201357.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2016 | RCV001197225.2 |
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. |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003824810.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Basal ganglia calcification, idiopathic, 4
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367862.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP4.
|
|
|
Pathogenic
(Feb 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329949.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect (constitutive activation of the PDGFRB gene and sensitivity to tyrosine kinase inhibitors) (Arts et al., 2016); Not observed … (more)
Published functional studies demonstrate a damaging effect (constitutive activation of the PDGFRB gene and sensitivity to tyrosine kinase inhibitors) (Arts et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23731542, 28286173, 28334876, 23731537, 25158255, 26455322, 28496993, 28183292, 30103666, 31291054, 32500973) (less)
|
|
|
Pathogenic
(Feb 12, 2013)
|
criteria provided, single submitter
Method: research
|
Myofibromatosis, infantile, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000256759.1
First in ClinVar: Oct 19, 2015 Last updated: Oct 19, 2015 |
Comment:
This variant has been found in all 11 individuals with familial infantile myofibromatosis studied.
Number of individuals with the variant: 11
Family history: yes
Sex: mixed
|
|
|
Pathogenic
(Dec 01, 2016)
|
criteria provided, single submitter
Method: research, in vitro
|
Infantile myofibromatosis
(Sporadic)
Affected status: yes, not applicable
Allele origin:
somatic,
not applicable
|
Demoulin lab, University of Louvain
Accession: SCV000484410.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Comment:
This mutation was found in one patient with myofibromatosis in our cohort and had been reported by others. The p.R561C mutant weakly activates PDGFRB signaling … (more)
This mutation was found in one patient with myofibromatosis in our cohort and had been reported by others. The p.R561C mutant weakly activates PDGFRB signaling in cell culture (gain of function). We sequenced PDGFRB in myofibromatosis cases using the Ion Torrent technology. The percentage of mutated reads (47%) suggests a germline change but normal DNA was not available to confirm this hypothesis, in the absence of familial history. All variants were confirmed by an alternative method (allele specific PCR or Sanger sequencing). Mutants were functionally characterized in experiments based on cell transfection. The p.R561C mutation was associated with a second somatic hit, c.1998C>A (p.N666K), which leads to full receptor activation in vitro. (less)
Observation 1:
Sex: male
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.
|
|
|
Pathogenic
(May 31, 2018)
|
criteria provided, single submitter
Method: curation
|
Myofibromatosis, infantile, 1
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000803486.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
This variant is interpreted as a Pathogenic, for Myofibromatosis, infantile, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines … (more)
This variant is interpreted as a Pathogenic, for Myofibromatosis, infantile, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:23731537). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23731537) (PMID:23731542). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in multiple unrelated patients (PMID:23731537,23731542,28183292). PS3 => Well-established functional studies show a deleterious effect (PMID:26455322). (less)
|
|
|
Pathogenic
(Mar 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Basal ganglia calcification, idiopathic, 4
Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome Infantile myofibromatosis Acroosteolysis-keloid-like lesions-premature aging syndrome
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.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000634672.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDGFRB function (PMID: 26455322, 28334876). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDGFRB function (PMID: 26455322, 28334876). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDGFRB protein function. ClinVar contains an entry for this variant (Variation ID: 55848). This missense change has been observed in individual(s) with infantile myofibromatosis (PMID: 23731537, 23731542, 28183292). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the PDGFRB protein (p.Arg561Cys). (less)
|
|
|
Pathogenic
(Jun 06, 2013)
|
no assertion criteria provided
Method: literature only
|
MYOFIBROMATOSIS, INFANTILE, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000077520.3
First in ClinVar: Jul 11, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
In affected members of 4 unrelated families with infantile myofibromatosis-1 (IMF1; 228550), Cheung et al. (2013) identified a heterozygous c.1681C-T transition in the PDGFRB gene, … (more)
In affected members of 4 unrelated families with infantile myofibromatosis-1 (IMF1; 228550), Cheung et al. (2013) identified a heterozygous c.1681C-T transition in the PDGFRB gene, resulting in an arg561-to-cys (R561C) substitution at a highly conserved residue. The families were of Chinese, European, French Canadian, and French origin, respectively. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing in the first 2 families, segregated with the phenotype in all families and was not found in several large control databases. Structural modeling indicated that the R561C mutation occurs in the cytoplasmic juxtamembrane (JM) region between the helical transmembrane segment and the kinase domain, and was predicted to compromise the autoinhibitory role of the JM domain, leading to increased kinase firing and promoting the formation of myofibromas in tissues with high PDGFRB signaling activity. In vitro functional studies were not performed. Martignetti et al. (2013) identified a heterozygous R561C mutation in the PDGFRB gene in affected members from 7 unrelated families with autosomal dominant infantile myofibromatosis. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control databases. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
Infantile myofibromatosis 1
Affected status: not provided
Allele origin:
germline
|
Center for Applied Genomics, Children's Hospital of Philadelphia
Accession: SCV000082631.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect (constitutive activation of the PDGFRB gene and sensitivity to tyrosine kinase inhibitors) (Arts et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23731542, 28286173, 28334876, 23731537, 25158255, 26455322, 28496993, 28183292, 30103666, 31291054, 32500973)
Comment:
This variant has been found in all 11 individuals with familial infantile myofibromatosis studied.
Comment:
This mutation was found in one patient with myofibromatosis in our cohort and had been reported by others. The p.R561C mutant weakly activates PDGFRB signaling in cell culture (gain of function). We sequenced PDGFRB in myofibromatosis cases using the Ion Torrent technology. The percentage of mutated reads (47%) suggests a germline change but normal DNA was not available to confirm this hypothesis, in the absence of familial history. All variants were confirmed by an alternative method (allele specific PCR or Sanger sequencing). Mutants were functionally characterized in experiments based on cell transfection. The p.R561C mutation was associated with a second somatic hit, c.1998C>A (p.N666K), which leads to full receptor activation in vitro.
Comment:
This variant is interpreted as a Pathogenic, for Myofibromatosis, infantile, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:23731537). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23731537) (PMID:23731542). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in multiple unrelated patients (PMID:23731537,23731542,28183292). PS3 => Well-established functional studies show a deleterious effect (PMID:26455322).
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDGFRB function (PMID: 26455322, 28334876). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDGFRB protein function. ClinVar contains an entry for this variant (Variation ID: 55848). This missense change has been observed in individual(s) with infantile myofibromatosis (PMID: 23731537, 23731542, 28183292). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the PDGFRB protein (p.Arg561Cys).
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. |
|---|---|---|---|---|
|
protein gain of function
|
|
|
Demoulin lab, University of Louvain
Accession: SCV000484410.1
|
|
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP4.
Comment:
Published functional studies demonstrate a damaging effect (constitutive activation of the PDGFRB gene and sensitivity to tyrosine kinase inhibitors) (Arts et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23731542, 28286173, 28334876, 23731537, 25158255, 26455322, 28496993, 28183292, 30103666, 31291054, 32500973)
Comment:
This variant has been found in all 11 individuals with familial infantile myofibromatosis studied.
Comment:
This mutation was found in one patient with myofibromatosis in our cohort and had been reported by others. The p.R561C mutant weakly activates PDGFRB signaling in cell culture (gain of function). We sequenced PDGFRB in myofibromatosis cases using the Ion Torrent technology. The percentage of mutated reads (47%) suggests a germline change but normal DNA was not available to confirm this hypothesis, in the absence of familial history. All variants were confirmed by an alternative method (allele specific PCR or Sanger sequencing). Mutants were functionally characterized in experiments based on cell transfection. The p.R561C mutation was associated with a second somatic hit, c.1998C>A (p.N666K), which leads to full receptor activation in vitro.
Comment:
This variant is interpreted as a Pathogenic, for Myofibromatosis, infantile, 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:23731537). PP1-Strong => PP1 upgraded in strength to Strong (PMID:23731537) (PMID:23731542). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in multiple unrelated patients (PMID:23731537,23731542,28183292). PS3 => Well-established functional studies show a deleterious effect (PMID:26455322).
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PDGFRB function (PMID: 26455322, 28334876). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PDGFRB protein function. ClinVar contains an entry for this variant (Variation ID: 55848). This missense change has been observed in individual(s) with infantile myofibromatosis (PMID: 23731537, 23731542, 28183292). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the PDGFRB protein (p.Arg561Cys).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis. | Arts FA | Human molecular genetics | 2017 | PMID: 28334876 |
| Case report: rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene. | Mudry P | BMC cancer | 2017 | PMID: 28183292 |
| PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. | Arts FA | Oncogene | 2016 | PMID: 26455322 |
| Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. | Martignetti JA | American journal of human genetics | 2013 | PMID: 23731542 |
| A recurrent PDGFRB mutation causes familial infantile myofibromatosis. | Cheung YH | American journal of human genetics | 2013 | PMID: 23731537 |
Text-mined citations for rs367543286 ...
HelpThese 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 Sep 29, 2024
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.