CLCN1

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

Basic information

Region (hg38): 7:143316110-143352083

Links

ENSG00000188037 ∙ NCBI:1180 ∙ OMIM:118425 ∙ HGNC:2019 ∙ Uniprot:P35523 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• myotonia congenita, autosomal dominant (Strong), mode of inheritance: AD
• myotonia congenita, autosomal recessive (Strong), mode of inheritance: AR
• Thomsen and Becker disease (Supportive), mode of inheritance: AD
• myotonia congenita, autosomal recessive (Strong), mode of inheritance: AR
• myotonia congenita, autosomal dominant (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Myotonia congenita, autosomal dominant; Myotonia congenita, autosomal recessive, Myotonia levior	AD/AR	Musculoskeletal; Pharmacogenomic	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	Musculoskeletal	1670657; 1379744; 7981750; 7951242; 8112288; 7581380; 9040658; 11113225; 11840191; 11933197; 12390967; 12699527; 14639587; 15786415; 17932099; 19185184; 18337100; 20842486; 20301529; 21221019

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CLCN1 gene.

• Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form (431 variants)
• not provided (404 variants)
• Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form (304 variants)
• Batten-Turner congenital myopathy (101 variants)
• Congenital myotonia, autosomal recessive form (94 variants)
• not specified (75 variants)
• Congenital myotonia, autosomal dominant form (54 variants)
• Inborn genetic diseases (32 variants)
• Tip-toe gait (11 variants)
• CLCN1-related condition (7 variants)
• Abnormality of the musculature (4 variants)
• Myotonia (3 variants)
• Smith-Lemli-Opitz syndrome (2 variants)
• 6 conditions (2 variants)
• CLCN1-related disorder (2 variants)
• Cerebral palsy (1 variants)
• EMG: myotonic discharges;Myotonia (1 variants)
• Autosomal dominant intermediate Charcot-Marie-Tooth disease (1 variants)
• Myotonia levior (1 variants)
• Myopathy;EMG: myopathic abnormalities (1 variants)
• Lumbar hyperlordosis;Hypoplasia of the maxilla;Skeletal muscle hypertrophy;Myotonia;Achilles tendon contracture (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CLCN1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		2	15	119	5	141
missense	23	48	370	10	5	456
nonsense	26	7	3			36
start loss						0
frameshift	39	12	3			54
inframe indel	1	2	6			9
splice donor/acceptor (+/-2bp)	14	18	1			33
splice region	1	2	28	17	1	49
non coding		1	12	78	44	135
Total	103	90	410	207	54

Highest pathogenic variant AF is 0.000269

Variants in CLCN1

This is a list of pathogenic ClinVar variants found in the CLCN1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-143316154-C-A		Congenital myotonia, autosomal recessive form	Uncertain significance (Feb 20, 2024)
7-143316192-C-T		Batten-Turner congenital myopathy • not specified • Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Benign/Likely benign (Jan 12, 2018)
7-143316197-C-G		not specified	Benign (Oct 31, 2016)
7-143316197-CTC-GGA			Benign (Apr 15, 2016)
7-143316198-T-G		not specified	Benign (Oct 31, 2016)
7-143316199-C-A		not specified	Benign (Oct 31, 2016)
7-143316221-A-G		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Likely benign (Jan 14, 2024)
7-143316225-C-T		not specified • Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Conflicting classifications of pathogenicity (Sep 13, 2022)
7-143316226-G-A		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Uncertain significance (Oct 08, 2022)
7-143316227-G-T		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Likely benign (Jul 19, 2023)
7-143316230-A-G		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Likely benign (Mar 18, 2023)
7-143316231-C-T		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Pathogenic (Jan 04, 2024)
7-143316236-G-A		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Likely benign (Oct 27, 2023)
7-143316237-C-A		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Uncertain significance (Aug 29, 2018)
7-143316238-G-A		Batten-Turner congenital myopathy • not specified • Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form • CLCN1-related disorder	Benign/Likely benign (Jan 31, 2024)
7-143316239-TG-T		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Pathogenic/Likely pathogenic (Aug 07, 2023)
7-143316244-G-C		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Uncertain significance (Feb 03, 2022)
7-143316245-T-C		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Likely benign (Nov 30, 2023)
7-143316246-GA-G		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Pathogenic (Jun 12, 2023)
7-143316249-C-A		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Uncertain significance (Oct 03, 2022)
7-143316255-T-C		Congenital myotonia, autosomal dominant form;Congenital myotonia, autosomal recessive form	Uncertain significance (Aug 24, 2023)
7-143316256-GGTGGGGTAGTGACCCCCAGTACCAGTATATGCCCTTTGAACACTGCACCAGCTACGGACTGCCCTCTGAGAATGGGGGCCTCCAGCACAGGCTCCGGAAGGATGCAGGCCCCCGCCACAACGTCCACCCCACACAGGTAAAGTGCTCTAAGGGGAGAGGGGAGCCATGGATGAGGGGAGACAGTGGTGCCAGAGACTGGTGAAAATGAGGAATTGGGTGAAAAGAGGGAGCAGTGTTACATTTTTTTAACTTAAAAAACAAGTACGTGGTGATGTGTTCAAAATATGAAAATCTTTGAAAGTCTGGGCTCACTTAAGTATGCACTTAGAGAGATATGCATGCACTTTCATACAACCTTTACCAACAGAGTACCCAAATCATATGGGGAAACAGCAGAGCCTCACATGCATGAATAGCTCGTGCTTACATAACCTACGTGGAGTGGATTGCGTAGGAGCCCACACTGCAGTGTGCTGGGAGCTGTCTCCCACACCCTCACCCACAGGTAGACACTGCCAGATTTCTGCCTCTGGGACCCTCTGCAGAATACACACAAACATGAATCTTTCTGCAGAAGGCAGAAGAAAGGAATTGGGCAAGTGTAGAAAACAGACTGAATTGCTTATCAGTGATCAAAGATCTACCAACGTCAAAATGAGCAGAGATGTACAAGCTTTTAGGTCGCAAGATGATCAAGTAAGAACCTATTAAGTGTTAGGCACCTGGAAAAGGGCAGAGATGTGATCCCAGCAACAGAAGCATGCAGGCTAATTAGGAGTGTCTATGGATGAGCAGCCTCCCGCTGTGGGATTGGTGGGATATGAACACCTAGGAAAGGGGGAATGGGGATGGGCACAACTAAAGGAAAGGTTGTGAAATTGTCATGGAAAAAGATAGGTCATGGTTAATAAGTAAGTGTGCCTCTCCCTCCAAAGAATGCAGAGAATAACAGAGGATAGAATTTGTCTAGAGGGCAGTTGGCCAGAACTTTTTTTTTTTTTTTTTTTTTTGAGATGGAGTCTCGCTCTGTCTCCCAGGCTGGAGTGCAGTGGTGCTATCTTGGCTCACTGCGACCTCCGCCTCCCGGGTTCAAGCAATTCTCTTTCCTCAGCCTCCTGAGTAGCTGGGATTACAAGCACCTGCCACCATACCTGGCAAATTTTTGTACTTTCAGTAGAGACGGGGTTTTGCCATGTTGGCCAGGCTGTCTCGAACTCCTGACCTCAGGTAATTCACCCGCCTTGGCCTCCCAAAGTGCTGGAATTACAGGTGTTAACCACTGTGCCCAGTCTGGTCAGAACTTAAAAGGCTTTTTTTTCTTTCTTTTTTTTTTTTTTAACAGGGAGCCTTCAGTTCCTTTAGGTTTAAGGCTGGGAAGCTGAGGCATGAGCTATGCAGGGGATCTCAGCACTGGGGGTCAAAAGGATCTGCTCTCAGTCCCTGACCAACCCCCAGGAGTATTTGCAAAGGCAGCGCTAGGGACCCAGTAGGGAAGAGGGACATACAGGTCAGTGTAGGCTGGAATCGAGCATTGGGAAGGTTTCTTGGAGACAGCGGGGTCTGACTAGGCCTTTGAACACTGTGTGGGATCAGCAGGAGGGAAGACCCCTCCCCCTGGCCCTGTGTTCTCACTCGTGTACATGGTTGTATCTGGGTGGGATGGCAACTTGAGTAACAGTGCCATTATGGCACTTCCTGATGACAGTTCTCGTGTTGGGAAGCTATGGTTAGTTTGGGGAGTAGAATTGGCCTGTTTTCTACAGGTCTCAAAAGTAAACAAGAGTTTGGATTAGTTTTTCTTTGTTTAATTTTTATTATGGAAGACTTACACAAAAATGGAATGGTATAGTGAAGCCCCAAGTACCCACCAGTTGTCAATATTTTGTCACTATTGTTCCATCTATTCTTCCCTTCCCCACCCTCACCACTCTACACACCATGGAATACTTTTTTTTTGTTTTTTGTTTTTTGTTTTTTGTTTTTGAGATGGAGTTTCGCTCTTGTTGCCCAGGCTGGAATGCAATGGCGCGATCTCAGCTCACCGCAATCTCCGCCTCCCTGGTTCAAGCAATTCTCCTGCCTCCGCCTCCCAGGTAGCTGAGATTACAGGCATGCGCCACCATGCCTGGCTAATTTTTGTATTTTTAGTAGAGACGAGGTTTCTCCATGTTGGTCAGGCTGGTCTTGATCTCCTGACCTCAGGTAACCTGCCCATCTCAGGCTCCTAAAGTGCTGGGGTTACAGGGGTGAGCCACTGAGCCTTGCTTCCACCTTGGAATACTTTTTAACAAATCCCAGACATTGTATCACTTGTAGACTTGAGTTTTGACTTCTCCCTTGCCCTCCCCTCACCCTGCCCTGCATGGGACCAGCCAGAACAGATCTGGCCCTTTAAGTGTTTTCCCAGCCCAGGTATGATGATATGAAGCAACCCCCTTCCTTGTCTCCACTGGCCTGGGGCCTTGAGGAGCTGAGACAGCCTCAGCTGTCTGACTTCCACTGGGAAGTATGTTCTCTCTCTGGGTCCCACGCAGGGTTTGGAAGGAAACACTGCCTCCCTCGGTCACTGACCCAGAAGACAAACAGCCATGAGCAGGGCAATTCATGTGCGTGCTTGTTCAGGACTGCGGTGTAAAATGCTGCTCATATTGTGAAATCAGATCTCTTCTACTCAGGCTCTCCCAGAATCCAGCAACATGGCCTGGCCTGACCCTGGCCCCAGAGGACAGTTAGTGTAGTGGGAGTGGGGCAGGCTAAAAGTGGTTGGAGCTCTTGTATACCCCACACAGACACACGTGCTCTGCCTCAGGATGGAAGCGGAGGGCCACCAGACCTGGGGGAGCTGCTCTGTCCTCTTCACATGTGGGGCAGGTAGGGGTCTAATTATCTAGCTGTGGGAAGAAGTAGATGGACCTGCCTTTTCGGGCTAGTTCTTGTGTGTGCATACAAGCACTGGGAGATGAAGTGGATGGTCTTGAAGCTTGATAGAGGACCTGAGGTGCCTCAGGTAAGGCTAGACACACCAAGGCAAAGTGCAACCAAGACTGCCCTGCTAGTTAGCCCAGTCTGTCCTCACCCTGTTCATGTTAGGAGAAAAGTCAATGCAAGTGGTCTGGGGAAATTGTGGGACATACAGAAAGCGCAGTGACACAAAACACCTGATTGATATGGCCACCTGGGTTCAGCACAGTTCTGTACCTCTGCTTCAAAGCAAAAACTGGCCTCCTTGATAAAGGCTACCCTGGATCAAGGTGAGTACAGGTTGGAGAATGGGTGTAGAGAAGGTAGGATGAATGAACAAGGGAAAGGGTGGGAAGTGTGGGAATGGAGGGTGGAGAGTAGAGGGCAGGGATGACCACAAAGTCACCCTGCATGCAGTCAACACCCAGAATTCAAAAAGCTGTTGTTCTTTTCTTCTGTGAGTCTGTCTGCTGGCCTCTGTCTATTATTTTTTTAGTCTTCCACAAGGCAGACACTGATCATTCTCTCTCTGTCCAGATTTATGGCCATCACAAAGAACAATTCTCAGACAGGGAGCAGGACATAGGGATGCCCAAGAAGACAGGCTCCAGTTCTACCGTGGACAGCAAGGATGAGGATCACTATTCTAAATGTCAAGGTGATGGGGACTGAGGAATAAAGAAATCTGGAGTAGAAACAGGTACAGGGATTAGGAGAATAACTTGGGCATCCCATTGCACGTACGTACTCCCTGCCCTGCTACAAAAACTCTCCTCTAATTGTTTTTAAGAGACAGGGTCTCACTCTGTCATTCAGACTGAAGTGCAGTGGAGTGATCATAGCTCACTGCAGCCTAGAACTCCTGGGCTCAAGTGATCCTCCTGCCTCAGCCTCTCCAGTAGCTGAGACTATAGGCACATGCCACCATGCCCAGCTAATTTTAAAACTTTTTTTGTAAGGATGCTGAGGCTGGTCTTGAACTCCTGGCATCAAGCAATCCTCCCGCCTTAGCCTCCCAAATTCCTGGGATTAGAGGCGTGAGCCACCATGCTTGGCCCCTCTAAGTATTAAGGAAAAGGCACCTCTCTTCACCTCCTTCGCACTTTGCCTATTCCCTGTTATTCCTCCCACAACTCCAAGAAATGAGTTTTAGGAAGGAATTCAAGTATTCATGGGGAACTGGGCTTTGGTGCCTTTTGCAGGGGCCGGAGCAGCAATCAGCAGAGGGGTAATGAGAAACTCAGTGCATAAGACATACGGACCCTGGGGGCCCAAGGCTTCCCCTCCCATCTTGGGTATAGCACCCAAAGTAAAGTAGTGACTCGTTAGCTGCTTTTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTCTGTCTCTACATATATATATTTTTGTTTGTTTGTTTGTTTGTTGTTTGTTTGTTTGTTTTTTCCCTCATCTCTTCCTAGATTGTATCCACCGCCTGGGACAGGTGGTGAGAAGAAAATTAGGGGAAGACGGGATCTTTCTGGTGCTTCTGGGACTGCTGATGGCTCTGGTCAGCTGGAGCATGGACTACGTCAGTGCCAAAAGCCTTCAGGGTAGGTTTAACCTGGACCTTTGCCCACAGCCGTTTCTGGAGTTTCTACCTAGGGTAAGCAGGGTGTGTTATCGGAAGCGAATGTTAAGCAGGGTGTGTTATGGGAAGCGAATATTGCGCAGAGAGGGATCAGGTGGGACTCCAGGCCCAGAAAAGACCAGACCCAGGCCTGCTCCACTTCTCACGCCCCTCCACTCACTGCCACCCAAGCAGTGGATGCCCCTCTAATAGGGTGGCCAACTTGCCCCAGTTCCCCAGGGACTTTCCCAGTTTCAGCACTGAACATCCCGAATCCCAGGAAGCCCCTTGGTTCTGGGCACACCGGGTGGTTGGTCACACCCAGGCCTCCAGACCCTGTACTCCA-G		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Pathogenic (May 25, 2018)
7-143316259-G-A		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form • Congenital myotonia, autosomal recessive form	Pathogenic/Likely pathogenic (Dec 03, 2023)
7-143316265-G-T		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form • Inborn genetic diseases • not specified	Uncertain significance (Feb 28, 2024)
7-143316268-AC-A		Congenital myotonia, autosomal recessive form;Congenital myotonia, autosomal dominant form	Pathogenic (Apr 08, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CLCN1	protein_coding	protein_coding	ENST00000343257	23	35958

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.25e-20	0.203	124887	8	853	125748	0.00343

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.212	529	543	0.974	0.0000306	6376
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00180	0.00173
Ashkenazi Jewish	0.00129	0.00129
East Asian	0.000218	0.000217
Finnish	0.0170	0.0169
European (Non-Finnish)	0.00355	0.00347
Middle Eastern	0.000218	0.000217
South Asian	0.000817	0.000784
Other	0.00361	0.00359

dbNSFP

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.
• Pathway: Stimuli-sensing channels;Ion channel transport;Transport of small molecules (Consensus)

Intolerance Scores

• loftool: 0.0794
• rvis_EVS: 0.21
• rvis_percentile_EVS: 67.52

Haploinsufficiency Scores

• pHI: 0.425
• hipred: N
• hipred_score: 0.229
• ghis: 0.520

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.128

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Clcn1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); reproductive system phenotype; growth/size/body region phenotype; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: muscle contraction;neuronal action potential propagation;ion transmembrane transport;regulation of ion transmembrane transport;chloride transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;chloride channel complex;sarcolemma
• Molecular function: voltage-gated chloride channel activity;protein binding;protein homodimerization activity