Submissions for variant NM_002609.4(PDGFRB):c.1681C>T (p.Arg561Cys)

gnomAD frequency: 0.00001  dbSNP: rs367543286

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000049264	SCV000256759	pathogenic	Myofibromatosis, infantile, 1	2013-02-12	criteria provided, single submitter	research	This variant has been found in all 11 individuals with familial infantile myofibromatosis studied.
GeneDx	RCV000390507	SCV000329949	pathogenic	not provided	2023-02-21	criteria provided, single submitter	clinical testing	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)
Demoulin lab, University of Louvain	RCV000454370	SCV000484410	pathogenic	Infantile myofibromatosis	2016-12-01	criteria provided, single submitter	research	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201357	SCV000634672	pathogenic	Acroosteolysis-keloid-like lesions-premature aging syndrome; Basal ganglia calcification, idiopathic, 4; Infantile myofibromatosis; Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome	2024-12-19	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 55848). 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) has been performed 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. Experimental studies have shown that this missense change affects PDGFRB function (PMID: 26455322, 28334876). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000049264	SCV000803486	pathogenic	Myofibromatosis, infantile, 1	2018-05-31	criteria provided, single submitter	curation	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197225	SCV001367862	pathogenic	Basal ganglia calcification, idiopathic, 4	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP4.
Revvity Omics, Revvity	RCV000390507	SCV003824810	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing
OMIM	RCV000049264	SCV000077520	pathogenic	Myofibromatosis, infantile, 1	2013-06-06	no assertion criteria provided	literature only
Center for Applied Genomics, Children's Hospital of Philadelphia	RCV000049264	SCV000082631	not provided	Myofibromatosis, infantile, 1		no assertion provided	not provided