CLCN1

protein-coding

chloride voltage-gated channel 1, the group of Chloride voltage-gated channels

Gene summary

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]

MANE transcript

NM_000083.3

Inheritance

AD, AR

ClinVar variants

P:420U:596B:378

Top phenotype

Myotonia congenita, autosomal dominant; Myotonia congenita, autosomal recessive, Myotonia levior

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr7:143,316,111-143,352,083

External References & Databases

Ensembl (ENSG00000188037)

Transcript & Mutation Effects

hg38 • Region Span ~36.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myotonia congenita, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008055

Submitter: Genomics England PanelApp

myotonia congenita, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009715

Submitter: Genomics England PanelApp

myotonia congenita, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008055

Submitter: Labcorp Genetics (formerly Invitae)

myotonia congenita, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009715

Submitter: Labcorp Genetics (formerly Invitae)

Thomsen and Becker diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009710

Submitter: Orphanet

Clinical Genomic Database (CGD)

Myotonia congenita, autosomal dominant; Myotonia congenita, autosomal recessive, Myotonia leviorAD/AR

Manifestation: Musculoskeletal

Intervention: Musculoskeletal; Pharmacogenomic

Rationale: Individuals may be at increased risk of potentially avoidable/manageable anesthesia reactions, and the disorder may not be clinically highly obvious prior to severe sequelae; Muscle stiffness may respond to medical treatment (eg, mexiletine, tocainide, procainamide, quinine, or phenytoin, as well as other agents); Depolarizing muscle relaxants (eg, suxamethonium), and other agents (eg, adrenaline, beta-adrenergic agonists, propranolol, colchicine) may aggravate myotonia

Refs: 1670657; 1379744; 7981750; 7951242; 8112288; 7581380; 9040658; 11113225; 11840191; 11933197; 12390967; 12699527; 14639587; 15786415; 17932099; 19185184; 18337100; 20842486; 20301529; 21221019

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLCN1 variants in ClinVar

40 Conditions Cataloged

Congenital myotonia, autosomal recessive formTotal: 1444

Congenital myotonia, autosomal dominant formTotal: 1422

not providedTotal: 482

not specifiedTotal: 142

Inborn genetic diseasesTotal: 129

CLCN1-related disorderTotal: 100

Batten-Turner congenital myopathyTotal: 89

Skeletal muscle channelopathyTotal: 29

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000083.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	2 clinvar	3 clinvar	18 clinvar	337 clinvar	2 clinvar	362
missense	37 clinvar	147 clinvar	571 clinvar	34 clinvar	5 clinvar	794
nonsense	39 clinvar	29 clinvar	3 clinvar			71
start loss						0
frameshift	64 clinvar	42 clinvar	4 clinvar			110
splice donor/acceptor (+/-2bp)	15 clinvar	42 clinvar				57
Total	157	263	596	371	7	1394

Highest pathogenic variant AF is 0.0022599935

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000083.3	RefSeq	NP_000074.3	23	MANE Select
ENST00000343257.7	Ensembl	ENSP00000339867.2	23	MANE Select
ENST00000432192.6	Ensembl	ENSP00000395949.2	6	Standard
ENST00000455478.6	Ensembl	ENSP00000400027.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Stimuli-sensing channels
Ion channel transport
Transport of small molecules

Biological Process

muscle contraction
neuronal action potential propagation
ion transmembrane transport
regulation of ion transmembrane transport
chloride transmembrane transport

Molecular Function

voltage-gated chloride channel activity
protein binding
protein homodimerization activity

Cellular Component

plasma membrane
integral component of plasma membrane
chloride channel complex
sarcolemma

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000343257
Coding exons: 23
Length: 35958
Individuals with no LoFs: 124887
Homozygous LoFs: 8
Heterozygous LoFs: 853
Defined: 125748
p: 0.00343

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.212	529	543	0.974	0.0000306	6376
Missense (PolyPhen)		205	216.08	0.94871		2606
Synonymous	-0.425	228	220	1.04	0.0000131	2031
Loss of Function	1.59	37	49.0	0.755	0.00000249	558

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00099	0.00092	rare
Latino/Admixed American	0.00081	0.00078	rare
Ashkenazi Jewish	0.0013	0.0013	notable
East Asian	0.00022	0.00022	rare
Finnish	0.017	0.017	notable
European (Non-Finnish)	0.0036	0.0035	notable
South Asian	0.00082	0.00078	rare
Other	0.0036	0.0036	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Voltage-gated chloride channel (PubMed:8112288, PubMed:9122265, PubMed:12456816). Plays an important role in membrane repolarization in skeletal muscle cells after muscle contraction. {ECO:0000269|PubMed:12456816, ECO:0000269|PubMed:22521272, ECO:0000269|PubMed:26007199, ECO:0000269|PubMed:26502825, ECO:0000269|PubMed:26510092, ECO:0000269|PubMed:7951242, ECO:0000269|PubMed:8112288, ECO:0000269|PubMed:9122265, ECO:0000269|PubMed:9736777}.;
Disease: DISEASE: Myotonia congenita, autosomal recessive (MCAR) [MIM:255700]: A non-dystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Most patients have symptom onset in the legs, which later progresses to the arms, neck, and facial muscles. Many patients show marked hypertrophy of the lower limb muscles. The autosomal recessive form (Becker disease) is more severe than the autosomal dominant one (Thomsen disease). {ECO:0000269|PubMed:10215406, ECO:0000269|PubMed:10644771, ECO:0000269|PubMed:11113225, ECO:0000269|PubMed:12661046, ECO:0000269|PubMed:1379744, ECO:0000269|PubMed:19697366, ECO:0000269|PubMed:22521272, ECO:0000269|PubMed:22641783, ECO:0000269|PubMed:26007199, ECO:0000269|PubMed:26096614, ECO:0000269|PubMed:26502825, ECO:0000269|PubMed:26510092, ECO:0000269|PubMed:7874130, ECO:0000269|PubMed:7951242, ECO:0000269|PubMed:7981681, ECO:0000269|PubMed:8533761, ECO:0000269|PubMed:8571958, ECO:0000269|PubMed:8845168, ECO:0000269|PubMed:9566422, ECO:0000269|PubMed:9736777}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.0794
RVIS EVS: 0.21
RVIS percentile EVS: 67.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.128

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium