CLCN1

Chr 7

chloride voltage-gated channel 1

Also known as: CLC1

NCBI Gene: 1180ENSG00000188037UniProt: P35523

The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

UniProtMyotonia congenita, autosomal dominant
UniProtMyotonia congenita, autosomal recessive
594
ClinVar variants
116
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— CLCN1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
116 Pathogenic / Likely Pathogenic· 191 VUS of 594 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.99LOEUF
pLI 0.000
Z-score 1.59
OE 0.76 (0.58–0.99)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.21Z-score
OE missense 0.97 (0.91–1.05)
529 obs / 542.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.76 (0.58–0.99)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.91–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.04
0≤1.21.6
LoF obs/exp: 37 / 49.0Missense obs/exp: 529 / 542.9Syn Z: -0.43

ClinVar Variant Classifications

594 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic71
VUS191
Likely Benign275
Benign2
Conflicting10
45
Pathogenic
71
Likely Pathogenic
191
VUS
275
Likely Benign
2
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
4
23
0
45
Likely Pathogenic
32
23
16
0
71
VUS
0
168
18
5
191
Likely Benign
0
1
116
158
275
Benign
0
0
2
0
2
Conflicting
—10
Total50196175163594

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CLCN1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — CLCN1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Guidelines on clinical presentation and management of nondystrophic myotonias.
Stunnenberg BC et al.·Muscle Nerve
2020Review
Translating genetic and functional data into clinical practice: a series of 223 families with myotonia.
Suetterlin K et al.·Brain
2022Cohort
Diagnostics in skeletal muscle channelopathies.
Vicino A et al.·Expert Rev Mol Diagn
2023Review
Clinical and genetic analysis and literature review of children with myotonia congenita due to CLCN1 mutations.
Wang X et al.·Ital J Pediatr
2025Review
Clinical and molecular characteristics of myotonia congenita in China: Case series and a literature review.
Li Y et al.·Channels (Austin)
2022Review
Congenital myotonia: a review of twenty cases and a new splice-site mutation in the CLCN1 gene.
Özgün N et al.·Turk J Pediatr
2020Review
Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people.
Meng YX et al.·Medicine (Baltimore)
2022Cohort
Coexistence of SCN4A and CLCN1 mutations in a family with atypical myotonic features: A clinical and functional study.
Vacchiano V et al.·Exp Neurol
2023Functional
Novel CLCN1 mutations and clinical features of Korean patients with myotonia congenita.
Moon IS et al.·J Korean Med Sci
2009Cohort
Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia.
Furby A et al.·Neuromuscul Disord
2014
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Non Dystrophic MyotoniaArrythmia, Cardiac

A Single Center Prospective Study in an Estimated 570 Patients Who Underwent Genetic Screening at UZ Brussel in the Context of a Primary Cardiac Arrhythmia. Patients Showing a Variant Class 3,4 or 5 in SCN4A or CLCN1 Will Undergo a Clinical and Electrophysiological Review After IC.

NOT YET RECRUITING
NCT07183059Phase NAUniversitair Ziekenhuis BrusselStarted 2025-12-15
Electromyography

External Resources

Links to major genomics databases and tools