# NM_005677.4(COLQ):c.201del (p.Phe67fs)

https://sugi.bio/variant/colq-p-phe67fs

## Summary

**COLQ p.Phe67fs (c.201del)** is classified **Likely pathogenic** in COLQ (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-03). No gnomAD frequency available for this variant; Associated with congenital myasthenic syndrome 5.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2470923539 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the COLQ gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to congenital myasthenic syndrome 5.

*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, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | COLQ is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Congenital myasthenic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neck muscle weakness — Very frequent (99-80%)
- Ptosis — Very frequent (99-80%)
- Dysphagia — Very frequent (99-80%)
- Poor suck — Very frequent (99-80%)
- Sudden episodic apnea — Very frequent (99-80%)
- Fatigable weakness — Very frequent (99-80%)
- Proximal muscle weakness — Very frequent (99-80%)
- Frontalis muscle weakness — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018210/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COLQ](https://sugi.bio/atlas/gene/COLQ/) |
| Protein change (HGVS p.) | p.Phe67fs |
| Coding change (HGVS c.) | c.201del |
| MANE Select transcript | [NM_005677](https://www.ncbi.nlm.nih.gov/nuccore/NM_005677) |
| dbSNP | [rs2470923539](https://www.ncbi.nlm.nih.gov/snp/rs2470923539/) |
| Variant type | Deletion |
| Location | chr3:15489543-15489543 (GRCh38) |
| ClinVar | [VCV2680859](https://www.ncbi.nlm.nih.gov/clinvar/variation/2680859/) |

**All HGVS expressions:** `NC_000003.11:g.15531050del`, `NC_000003.12:g.15489543del`, `NG_009032.2:g.37209del`, `NM_005677.4:c.201del`, `NM_080538.2:c.171del`, `NM_080539.4:c.201del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 0.777, GERP -1.57, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.902, pLI 6.171e-12. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 17**, 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}

**COLQ** population constraint: LOEUF 0.902, pLI 6.171e-12, missense-Z -0.16893; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}

Residue **67** lies in the 'prad' region.

AlphaFold model confidence (whole protein): pLDDT 55.25, 3% of residues very-high.

**2 experimental structure(s)** (PDB): [13CO](https://www.rcsb.org/structure/13CO), [1VZJ](https://www.rcsb.org/structure/1VZJ).

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

*Describes the biological roles of COLQ (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:** COLQ's established molecular role includes molecular adaptor activity. p.Phe67fs falls in the prad region.


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

**Molecular function:** molecular adaptor activity.

**Biological process:** negative regulation of synaptic transmission, cholinergic, protein localization to synapse.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-03.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-08-03 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 5](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-5/).

**Reported phenotype names (ClinVar):** Congenital myasthenic syndrome 5.

## Similar variants {#similar}

Related COLQ variant pages (same residue, condition, or type): [COLQ p.Asn298fs](/variant/colq-p-asn298fs), [COLQ p.Asp377fs](/variant/colq-p-asp377fs), [COLQ p.Gly126fs](/variant/colq-p-gly126fs), [COLQ p.Gly198fs](/variant/colq-p-gly198fs), [COLQ p.Leu331fs](/variant/colq-p-leu331fs), [COLQ p.Met276fs](/variant/colq-p-met276fs), [COLQ p.Pro361fs](/variant/colq-p-pro361fs), [COLQ c.106+2_106+10del](/variant/colq-c-106-plus-2-106-plus-10del).

### 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 2680859). 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.*