ClinVar Miner

Submissions for variant NM_002609.4(PDGFRB):c.1681C>T (p.Arg561Cys) (rs367543286)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000049264 SCV000256759 pathogenic Infantile myofibromatosis 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 2018-12-14 criteria provided, single submitter clinical testing The R561C pathogenic variant in the PDGFRB gene has been reported previously in families with autosomal dominant infantile myofibromatosis (Cheung et al., 2013; Martingnetti et al., 2013). The heterozygous R561C variant has also been identified in two siblings with infantile myofibromatosis and their unaffected mother, suggesting incomplete penetrance (Linhares et al., 2014). Functional studies of R561C indicate it leads to constitutive activation the PDGFRB gene, is sensitive to tyrosine kinase inhibitors, and has ability for cell transformation and inducing cancer in immunodeficient mice (Arts et al., 2016). The R561C variant is not observed in large population cohorts (Lek et al., 2016). The R561C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R561C as a pathogenic variant.
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.
Invitae RCV001201357 SCV000634672 pathogenic Premature aging syndrome, Penttinen type; Basal ganglia calcification, idiopathic, 4; Infantile myofibromatosis; Kosaki overgrowth syndrome 2020-07-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 561 of the PDGFRB protein (p.Arg561Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs367543286, ExAC no frequency). This variant has been reported to segregate with infantile myofibromatosis in several unrelated families (PMID: 23731537, 23731542, 28183292). In one of these families, the variant was also shown to arise de novo in the proband. This variant has also been observed in two affected siblings, as well as in the unaffected mother (PMID: 25158255), suggesting incomplete penetrance. ClinVar contains an entry for this variant (Variation ID: 55848). Experimental studies have shown that this missense change results in the constitutive activation of the PDGFR pathway in the absence of ligand (PMID: 26455322, 28334876). For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000049264 SCV000803486 pathogenic Infantile myofibromatosis 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.
OMIM RCV000049264 SCV000077520 pathogenic Infantile myofibromatosis 1 2013-06-06 no assertion criteria provided literature only
Center for Applied Genomics,Children's Hospital of Philadelphia RCV000049264 SCV000082631 not provided Infantile myofibromatosis 1 no assertion provided not provided

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