rs1060499542

Positions:

• chr5-150125556-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_002609.4(PDGFRB):​c.1696T>C​(p.Trp566Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W566?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PDGFRB NM_002609.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 9.32

Genes affected

PDGFRB (HGNC:8804): (platelet derived growth factor receptor beta) The protein encoded by this gene is a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer (PDGFB or PDGFD) or a heterodimer (PDGFA and PDGFB). This gene is essential for normal development of the cardiovascular system and aids in rearrangement of the actin cytoskeleton. This gene is flanked on chromosome 5 by the genes for granulocyte-macrophage colony-stimulating factor and macrophage-colony stimulating factor receptor; all three genes may be implicated in the 5-q syndrome. A translocation between chromosomes 5 and 12, that fuses this gene to that of the ETV6 gene, results in chronic myeloproliferative disorder with eosinophilia. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150125556-A-K is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 5-150125556-A-G is Pathogenic according to our data. Variant chr5-150125556-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375682.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr5-150125556-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDGFRB	NM_002609.4	c.1696T>C	p.Trp566Arg	missense_variant	12/23	ENST00000261799.9	NP_002600.1
PDGFRB	NM_001355016.2	c.1504T>C	p.Trp502Arg	missense_variant	11/22		NP_001341945.1
PDGFRB	NM_001355017.2	c.1213T>C	p.Trp405Arg	missense_variant	12/23		NP_001341946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDGFRB	ENST00000261799.9	c.1696T>C	p.Trp566Arg	missense_variant	12/23	1	NM_002609.4	ENSP00000261799	P1
PDGFRB	ENST00000520579.5	c.*1010T>C		3_prime_UTR_variant, NMD_transcript_variant	12/23	1		ENSP00000430026
PDGFRB	ENST00000520229.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	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 -

Dandy-Walker syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Hydrocephalus;C4551572:Myofibromatosis, infantile, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Dobyns Lab, Seattle Children's Research Institute

Feb 18, 2019

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2017

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 -

Infantile myofibromatosis Pathogenic:1

Pathogenic, no assertion criteria provided

in vitro;research

Demoulin lab, University of Louvain

Dec 01, 2016

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). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.57		Gain of disorder (P = 0.0025);
MVP		0.87
MPC		2.9
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.92
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060499542; hg19: chr5-149505119;