# NM_001242896.3(DEPDC5):c.3709del (p.Glu1237fs)

https://sugi.bio/variant/depdc5-p-glu1237fs

## Summary

**DEPDC5 p.Glu1237fs (c.3709del)** is classified **Pathogenic** in DEPDC5 (ClinVar, Single submitter, 1 submitter). No gnomAD frequency available for this variant; Associated with familial sleep-related hypermotor epilepsy.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2092986219 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DEPDC5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to familial sleep-related hypermotor epilepsy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Diagnostic panels | DEPDC5 is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Sleep-related hypermotor epilepsy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Nocturnal seizures — Very frequent (99-80%)
- Abnormal repetitive mannerisms — Frequent (79-30%)
- Paroxysmal dystonia — Frequent (79-30%)
- Involuntary movements — Frequent (79-30%)
- Urinary incontinence — Occasional (29-5%)
- Depression — Occasional (29-5%)
- Anxiety — Occasional (29-5%)
- Hyperventilation — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022703/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DEPDC5](https://sugi.bio/atlas/gene/DEPDC5/) |
| Protein change (HGVS p.) | p.Glu1237fs |
| Coding change (HGVS c.) | c.3709del |
| MANE Select transcript | [NM_001242896](https://www.ncbi.nlm.nih.gov/nuccore/NM_001242896) |
| dbSNP | [rs2092986219](https://www.ncbi.nlm.nih.gov/snp/rs2092986219/) |
| Variant type | Deletion |
| Location | chr22:31876169-31876169 (GRCh38) |
| ClinVar | [VCV873407](https://www.ncbi.nlm.nih.gov/clinvar/variation/873407/) |

**All HGVS expressions:** `NC_000022.10:g.32272155del`, `NC_000022.11:g.31876169del`, `NG_034067.1:g.127219del`, `NM_001136029.4:c.3682del`, `NM_001242896.3:c.3709del`, `NM_001242897.2:c.3409del`, `NM_001363852.2:c.3643del`, `NM_001363854.2:c.3475del`, `NM_001364318.2:c.3709del`, `NM_001364319.2:c.3475del`, `NM_001364320.2:c.3643del`, `NM_001369901.1:c.3625del`, `NM_001369902.1:c.3625del`, `NM_001369903.1:c.3616del`, `NM_014662.6:c.3616del`, `NR_146296.2:n.3881del`, `NR_157125.2:n.3606del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.949, GERP 2.58, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.403, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 37 of 43**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DEPDC5** population constraint: LOEUF 0.403, pLI 1, missense-Z 3.7429; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **focal epilepsy** — Definitive (AD)

## Protein context {#protein}

Residue **1237** lies in the dep domain.

AlphaFold model confidence (whole protein): pLDDT 65.22, 19% of residues very-high.

**11 experimental structure(s)** (PDB): [6CES](https://www.rcsb.org/structure/6CES), [6CET](https://www.rcsb.org/structure/6CET), [7T3A](https://www.rcsb.org/structure/7T3A), [7T3B](https://www.rcsb.org/structure/7T3B), [7T3C](https://www.rcsb.org/structure/7T3C), [8FW5](https://www.rcsb.org/structure/8FW5).

## What this gene does {#gene-function}

*Describes the biological roles of DEPDC5 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DEPDC5's established molecular role includes small GTPase binding. p.Glu1237fs falls in the dep domain.


### Pathways affected {#pathways}

DEPDC5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Amino acids regulate mTORC1](https://reactome.org/content/detail/R-HSA-9639288) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** small GTPase binding, protein-containing complex binding.

**Biological process:** cellular response to amino acid starvation, negative regulation of TORC1 signaling.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Cytogénomique, Hospices Civils de Lyon | Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[familial sleep-related hypermotor epilepsy](https://sugi.bio/atlas/disease/familial-sleep-related-hypermotor-epilepsy/).

**Reported phenotype names (ClinVar):** Familial sleep-related hypermotor epilepsy, Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy.

## Similar variants {#similar}

Related DEPDC5 variant pages (same residue, condition, or type): [DEPDC5 p.Gly1564_Asp1565insTer](/variant/depdc5-p-gly1564-asp1565inster), [DEPDC5 p.Glu1237Lys](/variant/depdc5-p-glu1237lys), [DEPDC5 p.Glu1237=](/variant/depdc5-p-glu1237), [DEPDC5 p.Thr864Met](/variant/depdc5-p-thr864met), [DEPDC5 p.Asn1362fs](/variant/depdc5-p-asn1362fs), [DEPDC5 p.Asn437fs](/variant/depdc5-p-asn437fs), [DEPDC5 p.Leu1356fs](/variant/depdc5-p-leu1356fs), [DEPDC5 p.Lys229fs](/variant/depdc5-p-lys229fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 873407). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*