NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg) AND Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 21, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001541889.2

Allele description [Variation Report for NM_002609.4(PDGFRB):c.1696T>C (p.Trp566Arg)]

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

Gene:

PDGFRB:platelet derived growth factor receptor beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q32

Genomic location:

Preferred name:

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

HGVS:

NC_000005.10:g.150125556A>G
NG_023367.1:g.35304T>C
NM_001355016.2:c.1504T>C
NM_001355017.2:c.1213T>C
NM_002609.4:c.1696T>CMANE SELECT
NP_001341945.1:p.Trp502Arg
NP_001341946.1:p.Trp405Arg
NP_002600.1:p.Trp566Arg
NC_000005.9:g.149505119A>G
NM_002609.3:c.1696T>C

Protein change:

W405R; TRP566ARG

Links:

OMIM: 173410.0007; dbSNP: rs1060499542

NCBI 1000 Genomes Browser:

rs1060499542

Molecular consequence:

NM_001355016.2:c.1504T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001355017.2:c.1213T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002609.4:c.1696T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

protein gain of function [Variation Ontology: 0040]

Condition(s)

Name:: Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome
Synonyms:: SKELETAL OVERGROWTH WITH FACIAL DYSMORPHISM, HYPERELASTIC SKIN, WHITE MATTER LESIONS, AND NEUROLOGIC DETERIORATION; Kosaki overgrowth syndrome
Identifiers:: MONDO: MONDO:0014704; MedGen: C4225270; OMIM: 616592

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001759961	OMIM	no assertion criteria provided	Pathogenic (Jul 20, 2021)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002768630	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 21, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28639748, 30941910, 31004414, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001759961

OMIM

no assertion criteria provided

Pathogenic
(Jul 20, 2021)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002768630

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 21, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Expansion of the phenotype of Kosaki overgrowth syndrome.

Minatogawa M, Takenouchi T, Tsuyusaki Y, Iwasaki F, Uehara T, Kurosawa K, Kosaki K, Curry CJ.

Am J Med Genet A. 2017 Sep;173(9):2422-2427. doi: 10.1002/ajmg.a.38310. Epub 2017 Jun 22.

PubMed [citation]

PMID:: 28639748

Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome.

Zarate YA, Boccuto L, Srikanth S, Pauly R, Ocal E, Balmakund T, Hinkle K, Stefans V, Schaefer GB, Collins RT 2nd.

Am J Med Genet A. 2019 Jun;179(6):1047-1052. doi: 10.1002/ajmg.a.61145. Epub 2019 Apr 2. Review.

PubMed [citation]

PMID:: 30941910

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV001759961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 unrelated females with Kosaki overgrowth syndrome (KOGS; 616592), Minatogawa et al. (2017) identified heterozygosity for a c.1696T-C transition (c.1696T-C, NM_002609.3) in exon 12 of the PDGFRB gene, resulting in a trp566-to-arg (W566R) substitution in the juxtamembrane domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. The mutation occurred de novo in patient 1, and was not present in the unaffected mother and sister of patient 2. The variant was not present in the ExAC and gnomAD databases.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768630.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 27, 2023

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