# NM_001195553.2(DCX):c.628del (p.Val210fs)

https://sugi.bio/variant/dcx-p-val210fs

## Summary

**DCX p.Val210fs (c.628del)** is classified **Pathogenic** in DCX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-28). No gnomAD frequency available for this variant; Associated with lissencephaly type 1 due to doublecortin gene mutation.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2147262801 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the DCX gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to lissencephaly type 1 due to doublecortin gene mutation.

*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) | X-linked recessive |
| Age of onset (of this condition) | Adolescent, Childhood, Infancy, Neonatal |
| Diagnostic panels | DCX is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Lissencephaly type 1 due to doublecortin gene mutation** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Atypical behavior — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Language impairment — Very frequent (99-80%)
- Cognitive impairment — Very frequent (99-80%)
- Pachygyria — Frequent (79-30%)
- Flexion contracture — Frequent (79-30%)
- Generalized-onset seizure — Frequent (79-30%)
- Abnormal muscle tone — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006914/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DCX](https://sugi.bio/atlas/gene/DCX/) |
| Protein change (HGVS p.) | p.Val210fs |
| Coding change (HGVS c.) | c.628del |
| MANE Select transcript | [NM_001195553](https://www.ncbi.nlm.nih.gov/nuccore/NM_001195553) |
| dbSNP | [rs2147262801](https://www.ncbi.nlm.nih.gov/snp/rs2147262801/) |
| Variant type | Deletion |
| Location | chrX:111401067-111401067 (GRCh38) |
| ClinVar | [VCV1342885](https://www.ncbi.nlm.nih.gov/clinvar/variation/1342885/) |

**All HGVS expressions:** `NC_000023.10:g.110644295del`, `NC_000023.11:g.111401067del`, `NG_011750.1:g.16112del`, `NM_000555.3:c.871del`, `NM_001195553.2:c.628del`, `NM_001369370.1:c.628del`, `NM_001369371.1:c.628del`, `NM_001369372.1:c.628del`, `NM_001369373.1:c.628del`, `NM_001369374.1:c.628del`, `NM_178151.3:c.628del`, `NM_178152.3:c.628del`, `NM_178153.3:c.628del`

## 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 11.261, GERP 2.09, 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, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 7**, 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}

**DCX** population constraint: 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):

- **lissencephaly spectrum disorders** — Definitive (XL)

## Protein context {#protein}

Residue **210** lies in the doublecortin 2 domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 67.19, 10% of residues very-high.

**14 experimental structure(s)** (PDB): [1MJD](https://www.rcsb.org/structure/1MJD), [2BQQ](https://www.rcsb.org/structure/2BQQ), [2XRP](https://www.rcsb.org/structure/2XRP), [4ATU](https://www.rcsb.org/structure/4ATU), [5IKC](https://www.rcsb.org/structure/5IKC), [5IN7](https://www.rcsb.org/structure/5IN7).

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

*Describes the biological roles of DCX (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:** DCX's established molecular role includes microtubule binding. p.Val210fs falls in the doublecortin 2 domain.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neurofascin interactions](https://reactome.org/content/detail/R-HSA-447043) | electronic |

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

**Molecular function:** microtubule binding, protein kinase binding.

**Biological process:** neuron migration.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-28.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-28 |

## Associated conditions {#conditions}

[lissencephaly type 1 due to doublecortin gene mutation](https://sugi.bio/atlas/disease/lissencephaly-type-1-due-to-doublecortin-gene-mutation/).

**Reported phenotype names (ClinVar):** Lissencephaly type 1 due to doublecortin gene mutation, LISSENCEPHALY, X-LINKED, 1, LISSENCEPHALY AND AGENESIS OF CORPUS CALLOSUM.

## Same-residue context {#hotspot}

Residue **210** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [DCX p.Val210Phe](/variant/dcx-p-val210phe). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related DCX variant pages (same residue, condition, or type): [DCX c.705_705+12del](/variant/dcx-c-705-705-plus-12del), [DCX p.Phe57_Gly61delinsLeu](/variant/dcx-p-phe57-gly61delinsleu), [DCX p.Phe57fs](/variant/dcx-p-phe57fs), [DCX p.Pro288fs](/variant/dcx-p-pro288fs), [DCX p.Thr14fs](/variant/dcx-p-thr14fs), [DCX p.Val210Phe](/variant/dcx-p-val210phe), [DCX p.Leu356fs](/variant/dcx-p-leu356fs), [DCX c.809-1G>A](/variant/dcx-c-809-minus-1g-a).

### 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 1342885). 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.*