ClinVar Genomic variation as it relates to human health
NM_001242896.3(DEPDC5):c.856C>T (p.Arg286Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001242896.3(DEPDC5):c.856C>T (p.Arg286Ter)
Variation ID: 2580197 Accession: VCV002580197.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.2 22: 31797688 (GRCh38) [ NCBI UCSC ] 22: 32193674 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 23, 2023 Feb 20, 2024 Sep 8, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001242896.3:c.856C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001229825.1:p.Arg286Ter nonsense NM_001007188.4:c.856C>T NP_001007189.1:p.Arg286Ter nonsense NM_001136029.4:c.856C>T NP_001129501.1:p.Arg286Ter nonsense NM_001242897.2:c.856C>T NP_001229826.1:p.Arg286Ter nonsense NM_001363852.2:c.856C>T NP_001350781.1:p.Arg286Ter nonsense NM_001363854.2:c.856C>T NP_001350783.1:p.Arg286Ter nonsense NM_001364318.2:c.856C>T NP_001351247.1:p.Arg286Ter nonsense NM_001364319.2:c.856C>T NP_001351248.1:p.Arg286Ter nonsense NM_001364320.2:c.856C>T NP_001351249.1:p.Arg286Ter nonsense NM_001369901.1:c.772C>T NP_001356830.1:p.Arg258Ter nonsense NM_001369902.1:c.772C>T NP_001356831.1:p.Arg258Ter nonsense NM_001369903.1:c.856C>T NP_001356832.1:p.Arg286Ter nonsense NM_014662.6:c.856C>T NP_055477.1:p.Arg286Ter nonsense NR_110988.2:n.1062C>T non-coding transcript variant NR_146296.2:n.945C>T non-coding transcript variant NR_157125.2:n.945C>T non-coding transcript variant NR_157126.2:n.945C>T non-coding transcript variant NR_157128.1:n.1062C>T non-coding transcript variant NC_000022.11:g.31797688C>T NC_000022.10:g.32193674C>T NG_034067.1:g.48738C>T - Protein change
- R258*
- Other names
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R286*
- Canonical SPDI
- NC_000022.11:31797687:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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- 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 | ||
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| HI score
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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. |
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| DEPDC5 | - | - |
GRCh38 GRCh37 |
2337 | 2368 | |
Conditions - Germline
| Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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. |
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| Pathogenic (3) |
criteria provided, single submitter
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Nov 18, 2021 | RCV003329185.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2023 | RCV003329485.5 | |
| Pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2018 | RCV003329484.3 |
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
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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. |
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Pathogenic
(Nov 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Epilepsy, familial focal, with variable foci 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811589.2
First in ClinVar: Dec 31, 2022 Last updated: Sep 30, 2023 |
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Pathogenic
(Oct 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000890379.2
First in ClinVar: Mar 19, 2019 Last updated: Sep 30, 2023 |
Comment:
The R286X nonsense variant in the DEPDC5 gene has been reported previously in association with epilepsy (Bagnall et al., 2015; Ribierre et al., 2018). This … (more)
The R286X nonsense variant in the DEPDC5 gene has been reported previously in association with epilepsy (Bagnall et al., 2015; Ribierre et al., 2018). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R286X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, this variant is considered a pathogenic variant, and its presence is consistent with a DEPDC5-related disorder. (less)
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Pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial focal epilepsy with variable foci
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000546499.10
First in ClinVar: Oct 07, 2016 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 264725). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 264725). This premature translational stop signal has been observed in individual(s) with familial focal epilepsy with variable foci (PMID: 26704558). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg286*) in the DEPDC5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DEPDC5 are known to be pathogenic (PMID: 23542697, 23542701). (less)
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Pathogenic
(Dec 08, 2023)
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no assertion criteria provided
Method: literature only
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EPILEPSY, FAMILIAL FOCAL, WITH VARIABLE FOCI 1
Affected status: not provided
Allele origin:
unknown
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OMIM
Accession: SCV004035951.2
First in ClinVar: Sep 23, 2023 Last updated: Dec 17, 2023 |
Comment on evidence:
In a 6-year-old child with familial focal epilepsy with variable foci-1 (FFEVF1; 604364) and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a … (more)
In a 6-year-old child with familial focal epilepsy with variable foci-1 (FFEVF1; 604364) and focal cortical dysplasia type IIa, Ribierre et al. (2018) identified a heterozygous germline c.856C-T transition (c.856C-T, NM_001242896) in the DEPDC5 gene, resulting in an arg286-to-ter (R286X) substitution. The mutation, which was found sequencing of a gene panel and confirmed by Sanger sequencing, was inherited from the unaffected mother; it was not present in the gnomAD database. Analysis of resected brain tissue from the patient showed a somatic mosaic heterozygous c.865C-T transition in the DEPDC5 gene, resulting in a gln289-to-ter (Q289X) substitution that was in trans with the R286X mutation. The Q289X mutation was also absent from gnomAD. The somatic mosaic mutation was present in the cortical seizure-onset zone, but not in the surrounding cortical epileptic zone or in blood. These findings were consistent with biallelic inactivation of DEPDC5 in this patient. Neurons in the resected brain specimen showed increased phosphorylation of RPS6 (180460), consistent with increased mTOR (601231) activity. Ribierre et al. (2018) found that mouse embryos with focal mosaic knockdown of the Depdc5 gene in postmitotic neurons, generated by in utero electrocorporation and CRISPR/Cas9 gene editing, demonstrated impaired neuronal radial migration to the cortical plate. The mutant neurons were round and balloon-like, similar to dysmorphic neurons found in focal cortical dysplasia IIa. These abnormalities were associated with increased mTOR activity, and the neuronal migration defects could be prevented by treatment with the mTOR inhibitor rapamycin. Focal mosaic mutant mice showed increased susceptibility to focal seizures, and some showed seizure-related death, reminiscent of sudden expected death in epilepsy (SUDEP). Pyramidal cells from mutant mice showed increased complexity of dendritic branching, hypertrophy of dendritic spins, and enhanced excitatory synaptic activity compared to controls. These findings indicated that complete inactivation of Depdc5 during brain development causes epilepsy with focal cortical malformations, and that biallelic DEPDC5 mutations, germline and brain somatic mosaic (representing Knudson's 2-hit hypothesis of disease mechanism), underlie the focal cortical dysplasia that is sometimes observed in this disorder. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Epilepsy, familial focal, with variable foci 1
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000321016.3
First in ClinVar: Oct 07, 2016 Last updated: Sep 30, 2023 |
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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. |
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| DEPDC5-Related Epilepsy. | Adam MP | - | 2023 | PMID: 27683934 |
| Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. | Ribierre T | The Journal of clinical investigation | 2018 | PMID: 29708508 |
| Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. | Bagnall RD | Annals of neurology | 2016 | PMID: 26704558 |
| Mutations of DEPDC5 cause autosomal dominant focal epilepsies. | Ishida S | Nature genetics | 2013 | PMID: 23542701 |
| Mutations in DEPDC5 cause familial focal epilepsy with variable foci. | Dibbens LM | Nature genetics | 2013 | PMID: 23542697 |
Text-mined citations for rs886039255 ...
HelpRecord last updated Nov 25, 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.