Submissions for variant NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)

dbSNP: rs1060499542

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497546	SCV000590605	pathogenic	not provided	2017-06-21	criteria provided, single submitter	clinical testing	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
Ambry Genetics	RCV000622279	SCV000741859	uncertain significance	Inborn genetic diseases	2016-10-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001541889	SCV002768630	pathogenic	Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome	2020-05-21	criteria provided, single submitter	clinical testing	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
Demoulin lab, University of Louvain	RCV000454367	SCV000484407	pathogenic	Infantile myofibromatosis	2016-12-01	no assertion criteria provided	research	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).
Dobyns Lab, Seattle Children's Research Institute	RCV000779640	SCV000916317	pathogenic	Myofibromatosis, infantile, 1; Hydrocephalus	2019-02-18	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001257994	SCV001434807	likely pathogenic	Dandy-Walker syndrome		no assertion criteria provided	research
OMIM	RCV001541889	SCV001759961	pathogenic	Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome	2021-07-20	no assertion criteria provided	literature only