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.
ClinVar Genomic variation as it relates to human health
NM_025000.4(DCAF17):c.436del (p.Ala147fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(14)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_025000.4(DCAF17):c.436del (p.Ala147fs)
Variation ID: 209146 Accession: VCV000209146.44
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 2q31.1 2: 171448795 (GRCh38) [ NCBI UCSC ] 2: 172305305 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 May 8, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_025000.4:c.436del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_079276.2:p.Ala147fs frameshift NM_025000.4:c.436delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001164821.2:c.436del NP_001158293.1:p.Ala147fs frameshift NM_001164821.2:c.436delC NR_028482.2:n.788del non-coding transcript variant NC_000002.12:g.171448795del NC_000002.11:g.172305305del NG_013038.2:g.19545del - Protein change
- A147fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:171448794:C:
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| DCAF17 | - | - |
GRCh38 GRCh37 |
466 | 551 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2022 | RCV000278884.27 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
May 8, 2023 | RCV000191077.26 | |
|
DCAF17-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 9, 2024 | RCV004757156.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 24, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hypogonadism, diabetes mellitus, alopecia, mental retardation and electrocardiographic abnormalities
(Autosomal recessive inheritance)
Affected status: unknown, yes
Allele origin:
germline
|
Baylor Genetics
Study: Adult_WES
Accession: SCV000245470.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015 |
Comment:
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, … (more)
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. (less)
Observation 1:
Number of individuals with the variant: 1
Family history: yes
Age: 20-29 years
Sex: male
Geographic origin: Middle East
Observation 2:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Middle East
|
|
|
Pathogenic
(May 05, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Woodhouse-Sakati syndrome
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000247163.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: research
|
Woodhouse-Sakati syndrome
Affected status: yes
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV003924291.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
|
|
|
Pathogenic
(Mar 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000340343.4
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(May 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002544118.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
DCAF17: PVS1, PM2, PM3:Supporting
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Woodhouse-Sakati syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018146.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV002568844.1
First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022 |
|
|
|
Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905513.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Dystonic disorder (present)
Sex: female
|
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000330033.6
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633545, 6876115, 26664771, 24015686, 29574468, 32033986, 32552793, 33543475, 31589614, 33144682, 33098801, 19026396) (less)
|
|
|
Pathogenic
(Aug 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Woodhouse-Sakati syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001416367.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Dec 01, 2008)
|
no assertion criteria provided
Method: literature only
|
WOODHOUSE-SAKATI SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020709.2
First in ClinVar: Apr 04, 2013 Last updated: May 06, 2019 |
Comment on evidence:
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), … (more)
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. (less)
|
|
|
Pathogenic
(Aug 25, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Woodhouse-Sakati syndrome
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132988.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
|
|
|
Pathogenic
(Jul 09, 2024)
|
no assertion criteria provided
Method: clinical testing
|
DCAF17-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005347691.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The DCAF17 c.436delC variant is predicted to result in a frameshift and premature protein termination (p.Ala147Hisfs*9). This variant has been reported in multiple families with … (more)
The DCAF17 c.436delC variant is predicted to result in a frameshift and premature protein termination (p.Ala147Hisfs*9). This variant has been reported in multiple families with autosomal recessive Woodhouse-Sakati syndrome (see for examples Alazami et al. 2008. PubMed ID: 19026396, Maddirevula et al. 2020. PubMed ID: 32552793, Nanda et al. 2014. PubMed ID: 24015686). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in DCAF17 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Woodhouse-Sakati syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000297808.3
First in ClinVar: May 29, 2016 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
DCAF17: PVS1, PM2, PM3:Supporting
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633545, 6876115, 26664771, 24015686, 29574468, 32033986, 32552793, 33543475, 31589614, 33144682, 33098801, 19026396)
Comment:
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.
Comment:
The DCAF17 c.436delC variant is predicted to result in a frameshift and premature protein termination (p.Ala147Hisfs*9). This variant has been reported in multiple families with autosomal recessive Woodhouse-Sakati syndrome (see for examples Alazami et al. 2008. PubMed ID: 19026396, Maddirevula et al. 2020. PubMed ID: 32552793, Nanda et al. 2014. PubMed ID: 24015686). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in DCAF17 are expected to be pathogenic. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
DCAF17: PVS1, PM2, PM3:Supporting
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633545, 6876115, 26664771, 24015686, 29574468, 32033986, 32552793, 33543475, 31589614, 33144682, 33098801, 19026396)
Comment:
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.
Comment:
The DCAF17 c.436delC variant is predicted to result in a frameshift and premature protein termination (p.Ala147Hisfs*9). This variant has been reported in multiple families with autosomal recessive Woodhouse-Sakati syndrome (see for examples Alazami et al. 2008. PubMed ID: 19026396, Maddirevula et al. 2020. PubMed ID: 32552793, Nanda et al. 2014. PubMed ID: 24015686). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in DCAF17 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Woodhouse-Sakati Syndrome. | Adam MP | - | 2021 | PMID: 27489925 |
| Molecular diagnostic experience of whole-exome sequencing in adult patients. | Posey JE | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26633545 |
| The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome. | Sheridan MB | Case reports in genetics | 2015 | PMID: 26664771 |
| Alopecia and hypotrichosis as characteristic findings in Woodhouse-Sakati syndrome: report of a family with mutation in the C2orf37 gene. | Nanda A | Pediatric dermatology | 2014 | PMID: 24015686 |
| Phenotypic heterogeneity in Woodhouse-Sakati syndrome: two new families with a mutation in the C2orf37 gene. | Ben-Omran T | American journal of medical genetics. Part A | 2011 | PMID: 21964978 |
| C2orf37 mutational spectrum in Woodhouse-Sakati syndrome patients. | Alazami AM | Clinical genetics | 2010 | PMID: 20507343 |
| Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. | Alazami AM | American journal of human genetics | 2008 | PMID: 19026396 |
| A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities. | Woodhouse NJ | Journal of medical genetics | 1983 | PMID: 6876115 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DCAF17 | - | - | - | - |
Text-mined citations for rs797045038 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.