NM_025000.4(DCAF17):c.436del (p.Ala147fs) AND Woodhouse-Sakati syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: May 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000191077.24

Allele description

NM_025000.4(DCAF17):c.436del (p.Ala147fs)

Gene:

DCAF17:DDB1 and CUL4 associated factor 17 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

2q31.1

Genomic location:

Preferred name:

NM_025000.4(DCAF17):c.436del (p.Ala147fs)

HGVS:

NC_000002.12:g.171448795del
NG_013038.2:g.19545del
NM_001164821.2:c.436del
NM_025000.4:c.436delMANE SELECT
NP_001158293.1:p.Ala147fs
NP_079276.2:p.Ala147fs
NC_000002.11:g.172305305del
NM_001164821.2:c.436delC
NM_025000.3:c.436delC
NM_025000.4:c.436delCMANE SELECT
NP_079276.2:p.Ala147HisfsTer9
NR_028482.2:n.788del

Protein change:

A147fs

Links:

OMIM: 612515.0001; dbSNP: rs797045038

NCBI 1000 Genomes Browser:

rs797045038

Molecular consequence:

NM_001164821.2:c.436del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_025000.4:c.436del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_028482.2:n.788del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Woodhouse-Sakati syndrome
Synonyms:: Extrapyramidal disorder, progressive, with primary hypogonadism, mental retardation, and alopecia; Progressive extrapyramidal disorder with primary hypogonadism and alopecia; Woodhouse and Sakati syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009419; MedGen: C0342286; Orphanet: 3464; OMIM: 241080

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020709	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2008)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 6876115, 19026396
SCV000245470	Baylor Genetics - Adult_WES	criteria provided, single submitter (Yang et al. 2013)	Pathogenic (Oct 24, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19026396, 24088041, 26633545
SCV000247163	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 5, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000297808	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 19026396, 21964978, 27489925
SCV001132988	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Aug 25, 2019)	germline	clinical testing
SCV001416367	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 15, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20507343, 19026396, 24015686, 26664771, 28492532
SCV002018146	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003924291	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	1	not provided	not provided	yes	clinical testing, research
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities.

Woodhouse NJ, Sakati NA.

J Med Genet. 1983 Jun;20(3):216-9.

PubMed [citation]

PMID:: 6876115
PMCID:: PMC1049050

Clinical whole-exome sequencing for the diagnosis of mendelian disorders.

Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, Braxton A, Beuten J, Xia F, Niu Z, Hardison M, Person R, Bekheirnia MR, Leduc MS, Kirby A, Pham P, Scull J, Wang M, Ding Y, Plon SE, Lupski JR, Beaudet AL, et al.

N Engl J Med. 2013 Oct 17;369(16):1502-11. doi: 10.1056/NEJMoa1306555. Epub 2013 Oct 2.

PubMed [citation]

PMID:: 24088041
PMCID:: PMC4211433

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000020709.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 7 affected members of 2 Saudi families with Woodhouse-Sakati syndrome (WDSKS; 241080), including 1 of the original families described by Woodhouse and Sakati (1983), Alazami et al. (2008) identified homozygosity for a 1-bp deletion (436delC) in exon 4 of the DCAF17 gene, predicted to cause a frameshift in the beta-isoform of the protein and result in premature termination. The authors stated that in the alpha-isoform, the 1-bp deletion was predicted to lie in the 5-prime UTR and was unlikely to be pathogenic. The mutation was subsequently identified in 6 additional Saudi families with the disorder, but not in 274 Saudi control chromosomes. SNP-based haplotype analysis confirmed a founder effect, and the deletion likely arose approximately 55 generations earlier.

#	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 Baylor Genetics - Adult_WES, SCV000245470.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	clinical testing (GTR000508680.4)	PubMed (3)
2	not provided	1	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (3)

Description

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 23-year-old male with diabetes, dystonia, coordination difficulties, thumb stiffening, ulnar deviation of the hand, hypernasal voice, hypothyroidism, hypogonadism, chronic facial and extremity edema and erythema, similarly affected sib (not tested). Variant pathogenic in recessive state; heterozygotes are carriers.

#	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	(GTR000508680.4)	1	not provided	1	not provided
2	germline	unknown	not provided	not provided	not provided	(GTR000508680.4)	1	not provided	1	not provided

From Genetic Services Laboratory, University of Chicago, SCV000247163.1

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

#	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

From GeneReviews, SCV000297808.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

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

From Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001132988.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Invitae, SCV001416367.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Ala147Hisfs*9) in the DCAF17 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCAF17 are known to be pathogenic (PMID: 19026396, 20507343). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individuals with Woodhouse-Sakati syndrome (PMID: 19026396, 24015686, 26664771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209146). For these reasons, this variant has been classified as Pathogenic.

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

From Revvity Omics, Revvity, SCV002018146.3

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

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV003924291.1

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

#	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: Jul 15, 2024

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