CLCN1

Summary

CLCN1 (chloride voltage-gated channel 1, HGNC:2019) is a protein-coding gene on chromosome 7q34, encoding Chloride channel protein 1 (P35523). Voltage-gated chloride channel involved in skeletal muscle excitability.

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.

Source: NCBI Gene 1180 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myotonia congenita, autosomal dominant (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 1,740 total — 169 pathogenic, 110 likely-pathogenic
• Phenotypes (HPO): 29
• MANE Select transcript: NM_000083

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2019
Approved symbol	CLCN1
Name	chloride voltage-gated channel 1
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	CLC1, ClC-1
Ensembl gene	ENSG00000188037
Ensembl biotype	protein_coding
OMIM	118425
Entrez	1180

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000343257, ENST00000432192, ENST00000455478, ENST00000495612, ENST00000650516, ENST00000958857

RefSeq mRNA: 1 — MANE Select: NM_000083 NM_000083

CCDS: CCDS5881

Canonical transcript exons

ENST00000343257 — 23 exons

Exon	Start	End
ENSE00001364122	143339253	143339322
ENSE00001365878	143342372	143342505
ENSE00001366658	143350372	143350476
ENSE00001367514	143346579	143346658
ENSE00001367807	143321365	143321493
ENSE00001369415	143319755	143319875
ENSE00001370303	143346911	143346949
ENSE00001371588	143351594	143352083
ENSE00001373649	143320664	143320795
ENSE00001375725	143346140	143346251
ENSE00001375903	143345521	143345762
ENSE00001376116	143332419	143332503
ENSE00001377211	143330772	143330897
ENSE00001377354	143332724	143332873
ENSE00001382800	143331232	143331316
ENSE00001384896	143339511	143339621
ENSE00001385163	143331551	143331652
ENSE00001387289	143350568	143350654
ENSE00001388085	143341929	143342142
ENSE00001391088	143323309	143323386
ENSE00003478852	143321715	143321848
ENSE00003624164	143324414	143324492
ENSE00003895565	143316111	143316392

Expression profiles

Bgee: expression breadth ubiquitous, 108 present calls, max score 89.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0842 / max 25.8151, expressed in 23 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81766	0.0842	23

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	89.74	gold quality
triceps brachii	UBERON:0001509	87.51	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.12	gold quality
skeletal muscle tissue	UBERON:0001134	84.66	gold quality
vastus lateralis	UBERON:0001379	84.19	silver quality
quadriceps femoris	UBERON:0001377	82.82	silver quality
muscle organ	UBERON:0001630	82.70	gold quality
biceps brachii	UBERON:0001507	82.67	gold quality
muscle of leg	UBERON:0001383	82.27	gold quality
gastrocnemius	UBERON:0001388	82.24	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.97	gold quality
olfactory bulb	UBERON:0002264	81.55	gold quality
type B pancreatic cell	CL:0000169	79.60	gold quality
muscle tissue	UBERON:0002385	78.95	gold quality
buccal mucosa cell	CL:0002336	78.90	silver quality
diaphragm	UBERON:0001103	78.40	gold quality
gluteal muscle	UBERON:0002000	78.39	silver quality
vena cava	UBERON:0004087	77.92	gold quality
male germ cell	CL:0000015	76.46	gold quality
sperm	CL:0000019	75.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.31	gold quality
body of tongue	UBERON:0011876	73.69	silver quality
deltoid	UBERON:0001476	73.30	silver quality
pharyngeal mucosa	UBERON:0000355	73.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	72.96	gold quality
nasal cavity epithelium	UBERON:0005384	72.96	gold quality
pericardium	UBERON:0002407	72.55	gold quality
subthalamic nucleus	UBERON:0001906	72.29	gold quality
heart right ventricle	UBERON:0002080	72.12	gold quality
dorsal plus ventral thalamus	UBERON:0001897	71.81	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RBPJ

Literature-anchored findings (GeneRIF, showing 40)

• Mutations, unusually common in Scandinavia, show genetic heterogeneity in myotonia congenita. (PMID:11840191)
• Review: Myotonia caused by mutations in the muscle chloride channel gene CLCN1. (PMID:11933197)
• partially hydrophobic pocket close to the chloride binding site is accessible from the cytoplasm, consistent with the observed intracellular block by 9-AC. (PMID:12691663)
• the carboxyl terminus of ClC-1 is not necessary for intracellular trafficking but is critical for channel function (PMID:14718533)
• Two novel missense mutations were found in CLCN1 in a Myotonia Congenita patient, one of which has its major effects on the common gate of the chloride channel. (PMID:15241802)
• Five mutations and three polymorphisms of skeletal muscle chloride channel gene (CLCN1) were identified in this study. Among these, three missense mutations (S471F, P575S, D644G) and one polymorphism (T736I) are novel and could be unique to the Taiwanese. (PMID:15311340)
• Co-injection of wild-type cRNA with alternative splice variants causing premature truncation at codon 283 or codon 257 reduced the current density & accelerated channel closure on repolarization of the membrane. (PMID:15623702)
• the phenotype depends on the mutation type to some extent, but this does not explain the fact that severity varies greatly between heterozygous family members and may even vary with time in the individual patient (PMID:15786415)
• gating of skeletal muscle ClC-1 chloride channels is regulated by cytoplasmic ATP-sensing domains (PMID:16027167)
• Deletion of the terminal 100 amino acids (N889X) in human ClC-1 (skeletal-muscle chloride channel) has minor consequences, whereas truncation by 110 or more amino acids (from Q879X) destroys channel function. (PMID:16321142)
• The experimental results revealed that among the three residues tested, K149 plays the most important role in controlling both the gating and the permeation functions of ClC-0. (PMID:16567465)
• Activity-induced weakness in recessive myotonia congenita with a novel (696+1G>A) mutation (PMID:16854622)
• These results further clarify the correlation between the mutations and their functional implications of CLCN1 channels. (PMID:17097617)
• first experimental investigation of structural changes resulting from myotonia-causing mutations. (PMID:17107341)
• in the presence of physiological concentrations of ATP, reduction of the intracellular pH inhibits the expressed CLC-1, mostly by decreasing the open probability of the common gate of the channel. (PMID:17664348)
• modulation of ClC-1 by ATP is a key component of this molecular mechanism (PMID:17693413)
• asymptomatic patients with CLCN1 mutations may at least partially account for the EMG disease phenotype. (PMID:17826470)
• F413C and A531V but not R894X mutation of CLC-1 cause defective endoplasmic reticulum export of CLC-1 proetein. (PMID:17990293)
• CLCN1 variants are likely to modulate clinical expression of cold-induced myotonia caused by a single SCN4A mutation in a large cohort of French Canadians. (PMID:17998485)
• The data suggest that the polymorphic changes may affect the function of CLCN1 in response to the treatment of chemical compounds. (PMID:18035046)
• Phenotypic variability of autosomal dominant myotonia congenita in a family with muscle chloride channel (CLCN1) mutation. (PMID:18220014)
• Human ClC-1, expressed in Xenopus oocytes is insensitive to intracellular ATP up to 10 mM, at both pH 7.3 and 6.2, and results have implications for the understanding of nucleotide regulation of CLC proteins and for the role of ClC-1 in muscle excitation. (PMID:18227271)
• study reports kindred featuring index patient posessing 2 copies of a dominantly inherited mutated CLCN1 allele with a novel phenotypic presentation; kindred is the initial demonstration of dosage effect of a dominant mutated allele in the CLCN1 gene (PMID:18263754)
• The significance of the 2 cystathionine beta-synthase domains in the carboxyl tail of CLCN1 in channel function in an effort to explain conflicting and anomalous results from other studies is reported. (PMID:18321245)
• Thirty-three French-Canadian families with non-dystrophic myotonia were identified.Thirteen mutations were identified in CLCN1 and five mutations were identified in SCN4A (PMID:18337100)
• CLCN1 and SCN4A mutation occurrence is associated with non-dystrophic myotonia. (PMID:18337730)
• The clinical spectrum for this family is in agreement with a clinical diagnosis of Becker myotonia. This was confirmed by molecular diagnosis where a new disease-causing mutation (Q412P) was found in the family and absent in 200 unaffected chromosomes. (PMID:18624224)
• frequency of heterozygous recessive CLCN1 mutations is disproportionally higher in currently diagnosed myotonic dystrophy type 2(DM2) patients from Finland & Germany compared to control population; frequency in DM1 patients was the same as in controls (PMID:18807109)
• Recessive CLCN1 mutation presenting in a Thomsen disease. (PMID:18816629)
• The clinical guidelines proposed may help clinicians working in outpatient clinics to perform a focused genetic analysis of either CLCN1 or SCN4A. (PMID:19211598)
• Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression. (PMID:19220292)
• A novel mutation, 568GG>TC(G190S) in the CLCN1 gene, is responsible for autosomal dominant myotonia congenita with a variable phenotypic spectrum. (PMID:19697366)
• A CLCN1 mutational analyses revealed nine different novel point mutations in Korean patients with myotonia congenita. (PMID:19949657)
• CLCN1 dysfunction alone does not result in skeletal muscle morphologic changes even in advanced stages of myotonia congenita, and MRI skeletal muscle alterations in myotonic dystrophy must be clear consequences of the dystrophic disease process (PMID:20047568)
• We investigated a 62-year-old man who had mild clinical features of myotonia congenita. He was found to have a novel heterozygous G-to-A nucleotide substitution at position 1652 in exon 15 of the CLCN1 gene. (PMID:20120005)
• hClC-1 mutants expressed in whole-cell patch-clamped HEK293 cells showed that elimination of the carboxyl side chain in the E232Q mutation prevents fast gate closure at all voltages but common gating is also eliminated. (PMID:20398785)
• A novel p.L2871 mutation in the CLCN1 gene is described in a Honduran boy with myotonia congenita; his unaffected father carries the same mutation, most likely reflecting autosomal-recessive myotonia congenita. (PMID:20399394)
• sequencing of CLCN1 gene in 2 families with myotonia congenita revealed heterozygous mutation (892G>A, resulting in A298T) in 1 family and compound heterozygous mutations (782A>G, resulting in Y261C;1679T>C, resulting in M560T)in the other family (PMID:21045501)
• Mutations in CLCN1 contributes to the pronounced variability in the myotonic phenotype. (PMID:21204798)
• Our data showed that slow activation gating of P480T ClC-1 mutation impaired the increment of chloride conductance during repetitive depolarization (PMID:21385601)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	clcn1b	ENSDARG00000012269
danio_rerio	clcn1a	ENSDARG00000062084
mus_musculus	Clcn1	ENSMUSG00000029862
rattus_norvegicus	Clcn1	ENSRNOG00000016917
drosophila_melanogaster	ClC-c	FBGN0036566
caenorhabditis_elegans		WBGENE00000532

Paralogs (8): CLCN6 (ENSG00000011021), CLCN4 (ENSG00000073464), CLCN7 (ENSG00000103249), CLCN3 (ENSG00000109572), CLCN2 (ENSG00000114859), CLCN5 (ENSG00000171365), CLCNKB (ENSG00000184908), CLCNKA (ENSG00000186510)

Protein

Protein identifiers

Chloride channel protein 1 — P35523 (reviewed: P35523)

Alternative names: Chloride channel protein, skeletal muscle

All UniProt accessions (4): P35523, A0A3B3IU72, H7C0N6, H7C1F4

UniProt curated annotations — full annotation on UniProt →

Function. Voltage-gated chloride channel involved in skeletal muscle excitability. Generates most of the plasma membrane chloride conductance in skeletal muscle fibers, stabilizes the resting membrane potential and contributes to the repolarization phase during action potential firing. Forms a homodimeric channel where each subunit has its own ion conduction pathway. Conducts double-barreled currents controlled by two types of gates, two fast glutamate gates that control each subunit independently and a slow common gate that opens and shuts off both subunits simultaneously. Has a significant open probability at muscle resting potential and is further activated upon membrane depolarization. Permeable to small monovalent anions with ion selectivity for chloride > thiocyanate > bromide > nitrate > iodide.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane. Sarcolemma. T-tubule.

Tissue specificity. Predominantly expressed in skeletal muscles.

Disease relevance. Myotonia congenita, autosomal dominant (MCAD) [MIM:160800] 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 dominant form (Thomsen disease) is less common and less severe than the autosomal recessive one (Becker disease). A milder form of autosomal dominant myotonia is characterized by isolated myotonia without muscle weakness, hypotrophy, or hypertrophy (myotonia levior). The disease is caused by variants affecting the gene represented in this entry. 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). The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Modulated by membrane voltage with depolarization favouring channel opening and hyperpolarization favouring channel closure. Inhibited by acidic pH and ATP binding due to a shift of voltage dependence of common gating to more positive voltages. Inhibited by 9-anthracene-carboxylic.

Miscellaneous. Each monomer is composed of 18 alpha helices arranged in an internal pseudo-symmetry with an inverted membrane orientation. Most helices do not traverse the membrane completely.

Similarity. Belongs to the chloride channel (TC 2.A.49) family. ClC-1/CLCN1 subfamily.

RefSeq proteins (1): NP_000074* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001807	ClC	Family
IPR002243	Cl_channel-1	Family
IPR014743	Cl-channel_core	Homologous_superfamily
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR050970	Cl_channel_volt-gated	Family

Pfam: PF00654

Catalyzed reactions (Rhea), 5 shown:

• chloride(in) = chloride(out) (RHEA:29823)
• nitrate(in) = nitrate(out) (RHEA:34923)
• iodide(out) = iodide(in) (RHEA:66324)
• thiocyanate(in) = thiocyanate(out) (RHEA:75347)
• bromide(in) = bromide(out) (RHEA:75383)

UniProt features (182 total): sequence variant 66, helix 26, intramembrane region 18, strand 14, topological domain 13, mutagenesis site 13, turn 7, transmembrane region 5, compositionally biased region 5, region of interest 3, short sequence motif 3, binding site 3, domain 2, chain 1, sequence conflict 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8WXI	ELECTRON MICROSCOPY	2.57
8WXJ	ELECTRON MICROSCOPY	2.68
6COY	ELECTRON MICROSCOPY	3.36
6COZ	ELECTRON MICROSCOPY	3.36
6QV6	ELECTRON MICROSCOPY	3.63
6QVC	ELECTRON MICROSCOPY	4
6QVU	ELECTRON MICROSCOPY	4.2
6QVB	ELECTRON MICROSCOPY	4.34
6QVD	ELECTRON MICROSCOPY	4.34

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35523-F1	68.34	0.28

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 232 (protopore gate)

Ligand- & substrate-binding residues (3): 189; 484; 578

Post-translational modifications (1): 886

Mutagenesis-validated functional residues (13):

Position	Phenotype
290	changed chloride channel activity; changed gating of the channel.
291	no effect on calcium channel activity.
291	loss of calcium channel activity.
496	changed gating of the channel.
499	changed gating of the channel.
499	no effect on gating of the channel.
500	no effect on channel function.
636	reduces the effect of adenosine nucleotides on common gate.
638	reduces the effect of adenosine nucleotides on common gate.
651	has normal sensitivity to adenosine nucleotides.
847	reduces the effect of adenosine nucleotides on common gate.
848	abrogates the effect of adenosine nucleotides on common gate.
849	has normal sensitivity to adenosine nucleotides.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 139 (showing top): GOBP_INORGANIC_ANION_TRANSPORT, MEF2_02, NFKB_Q6, GCM_PRKCG, NFKB_C, GOBP_CHLORIDE_TRANSPORT, GOBP_MUSCLE_CONTRACTION, AFFAR_YY1_TARGETS_DN, GOBP_MUSCLE_SYSTEM_PROCESS, CREBP1_01, MEF2_Q6_01, CTAWWWATA_RSRFC4_Q2, GOBP_TRANSMEMBRANE_TRANSPORT, SHEN_SMARCA2_TARGETS_DN, GOBP_REGULATION_OF_MEMBRANE_POTENTIAL

GO Biological Process (7): chloride transport (GO:0006821), muscle contraction (GO:0006936), neuronal action potential propagation (GO:0019227), chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (5): voltage-gated chloride channel activity (GO:0005247), protein homodimerization activity (GO:0042803), chloride channel activity (GO:0005254), protein binding (GO:0005515), chloride transmembrane transporter activity (GO:0015108)

GO Cellular Component (6): plasma membrane (GO:0005886), T-tubule (GO:0030315), chloride channel complex (GO:0034707), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), sarcolemma (GO:0042383)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
cellular anatomical structure	2
monoatomic anion transport	1
inorganic anion transport	1
muscle system process	1
transmission of nerve impulse	1
nervous system process	1
action potential propagation	1
chloride transport	1
monoatomic anion transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
chloride channel activity	1
voltage-gated monoatomic anion channel activity	1
identical protein binding	1
protein dimerization activity	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
binding	1
monoatomic anion transmembrane transporter activity	1
chloride transmembrane transport	1
membrane	1
cell periphery	1
sarcolemma	1
monoatomic ion channel complex	1
transmembrane transporter complex	1
plasma membrane	1

Protein interactions and networks

STRING

1153 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CLCN1	SCN4A	P35499	946
CLCN1	MBNL1	Q9NR56	933
CLCN1	CELF1	Q92879	931
CLCN1	MBNL2	Q5VZF2	901
CLCN1	MBNL3	Q9NUK0	897
CLCN1	DMPK	Q09013	878
CLCN1	ATP2A1	O14983	844
CLCN1	CNBP	P20694	819
CLCN1	TNNT3	P45378	785
CLCN1	LDB3	O75112	771
CLCN1	TNNT2	P45379	768
CLCN1	RYR1	P21817	749
CLCN1	SIX5	Q8N196	695
CLCN1	CACNA1S	Q13698	674
CLCN1	MTMR1	Q13613	645

IntAct

19 interactions, top by confidence:

A	B	Type	Score
CLCN1	APPBP2	psi-mi:“MI:0915”(physical association)	0.720
CLCN1	FAM9B	psi-mi:“MI:0915”(physical association)	0.560
CLCN1	PRDM5	psi-mi:“MI:0915”(physical association)	0.560
CLCN1	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
Prdm16	ESYT2	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
CLCN1	APPBP2	psi-mi:“MI:0915”(physical association)	0.000
CLCN1	PRDM5	psi-mi:“MI:0915”(physical association)	0.000
CLCN1	CIDEB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): APPBP2 (Two-hybrid), FAM9B (Two-hybrid), CLCN1 (Affinity Capture-Western), CLCN1 (Affinity Capture-Western), DDB1 (Affinity Capture-Western), CLCN1 (Affinity Capture-Western), CLCN1 (Synthetic Lethality), STIP1 (Reconstituted Complex), STIP1 (Affinity Capture-Western), FKBP8 (Reconstituted Complex), AHSA1 (Reconstituted Complex), FKBP8 (Affinity Capture-Western), AHSA1 (Affinity Capture-Western), CRBN (Affinity Capture-Western), CLCN1 (Affinity Capture-Western)

ESM2 similar proteins: A0A0G2K1Q8, A0AV02, A2A6C4, A5D7L5, A6QNW6, B1MTL0, B2RXE2, C1BKZ7, O18917, P04920, P0DX17, P13808, P16283, P23347, P23348, P35523, P35524, P48746, P48751, P58295, Q0P5V9, Q14940, Q15043, Q15477, Q3MJ16, Q504Y0, Q50L42, Q5FWH7, Q5RB85, Q5RD44, Q64347, Q6A4L1, Q6SJP2, Q761V0, Q8BXR1, Q8CJI3, Q8K0H7, Q8R420, Q8VI23, Q91WD2

Diamond homologs: A1A7K1, A4TPW7, A5F0D5, A6T4V9, A7FM08, A7MGR4, A7N6K9, A7ZHP7, A7ZM51, A7ZWA3, A8ALD3, A9MPK6, A9N0Q1, A9R1E4, B1IQI5, B1IQZ8, B1JK21, B1LEU5, B1LGV8, B1XD25, B1XF57, B2K549, B2U1Q2, B2U300, B4SUY5, B4TK31, B4TXQ7, B5BL83, B5F8R6, B5FHR3, B5FJ02, B5R3G7, B5RHE1, B5Y1L4, B5Z0D5, B5Z428, B6HZD1, B7L5E4, B7LGL7, B7LWB6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1740 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	169
Likely pathogenic	110
Uncertain significance	613
Likely benign	577
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069498	NM_000083.3(CLCN1):c.99C>A (p.Tyr33Ter)	Pathogenic
1070234	NM_000083.3(CLCN1):c.360del (p.Leu121fs)	Pathogenic
1070310	NM_000083.3(CLCN1):c.1235A>C (p.Gln412Pro)	Pathogenic
1072179	NM_000083.3(CLCN1):c.1472-2A>G	Pathogenic
1075850	NM_000083.3(CLCN1):c.200_215del (p.Glu67fs)	Pathogenic
1175773	NM_000083.3(CLCN1):c.771T>A (p.Tyr257Ter)	Pathogenic
1322086	NM_000083.3(CLCN1):c.1457del (p.Pro486fs)	Pathogenic
1322087	NM_000083.3(CLCN1):c.1287del (p.Asp429fs)	Pathogenic
1322088	NM_000083.3(CLCN1):c.410_411delinsGGA (p.Tyr137fs)	Pathogenic
1354004	NM_000083.3(CLCN1):c.2148dup (p.Glu717fs)	Pathogenic
1381093	NM_000083.3(CLCN1):c.443G>A (p.Trp148Ter)	Pathogenic
1393878	NM_000083.3(CLCN1):c.1791_1792del (p.Gln597fs)	Pathogenic
1402851	NM_000083.3(CLCN1):c.618C>A (p.Tyr206Ter)	Pathogenic
1403542	NM_000083.3(CLCN1):c.989dup (p.Ala331fs)	Pathogenic
1427478	NM_000083.3(CLCN1):c.2581del (p.Leu861fs)	Pathogenic
1429319	NC_000007.13:g.(?143013209)(143049107_?)del	Pathogenic
1432751	NM_000083.3(CLCN1):c.854-2A>G	Pathogenic
1434202	NM_000083.3(CLCN1):c.1910T>A (p.Leu637Ter)	Pathogenic
1449054	NM_000083.3(CLCN1):c.1281del (p.Leu427fs)	Pathogenic
1452613	NM_000083.3(CLCN1):c.1401+1G>A	Pathogenic
1453541	NM_000083.3(CLCN1):c.2045del (p.Ser682fs)	Pathogenic
1454866	NM_000083.3(CLCN1):c.1269dup (p.Ile424fs)	Pathogenic
1459940	NC_000007.13:g.(?143042594)(143044062_?)del	Pathogenic
1687485	NM_000083.3(CLCN1):c.2058C>A (p.Tyr686Ter)	Pathogenic
1697271	NM_000083.3(CLCN1):c.1438C>A (p.Pro480Thr)	Pathogenic
1697273	NM_000083.3(CLCN1):c.644A>G (p.Lys215Arg)	Pathogenic
1697274	NM_000083.3(CLCN1):c.938C>T (p.Ala313Val)	Pathogenic
1709983	NM_000083.3(CLCN1):c.918C>A (p.Phe306Leu)	Pathogenic
1723137	NM_000083.3(CLCN1):c.2015G>A (p.Arg672His)	Pathogenic
1723138	NM_000083.3(CLCN1):c.2014C>G (p.Arg672Gly)	Pathogenic

SpliceAI

3720 predictions. Top by Δscore:

Variant	Effect	Δscore
7:143319848:GA:G	donor_gain	1.0000
7:143320653:T:G	acceptor_gain	1.0000
7:143320662:A:AG	acceptor_gain	1.0000
7:143320662:AGATT:A	acceptor_gain	1.0000
7:143320663:G:GT	acceptor_gain	1.0000
7:143320663:GA:G	acceptor_gain	1.0000
7:143320663:GAT:G	acceptor_gain	1.0000
7:143320663:GATT:G	acceptor_gain	1.0000
7:143320663:GATTG:G	acceptor_gain	1.0000
7:143320792:CAGG:C	donor_loss	1.0000
7:143320793:AGGGT:A	donor_loss	1.0000
7:143320794:GG:G	donor_gain	1.0000
7:143320795:GG:G	donor_gain	1.0000
7:143320796:GTA:G	donor_loss	1.0000
7:143320797:T:A	donor_loss	1.0000
7:143321845:AGAG:A	donor_loss	1.0000
7:143321846:GAG:G	donor_gain	1.0000
7:143321847:AG:A	donor_loss	1.0000
7:143321848:GG:G	donor_loss	1.0000
7:143321849:G:GA	donor_loss	1.0000
7:143321850:T:A	donor_loss	1.0000
7:143330891:G:GT	donor_gain	1.0000
7:143331230:A:AG	acceptor_gain	1.0000
7:143331231:G:GG	acceptor_gain	1.0000
7:143339251:A:AG	acceptor_gain	1.0000
7:143339252:G:GG	acceptor_gain	1.0000
7:143339506:TCTAG:T	acceptor_loss	1.0000
7:143339507:CTAG:C	acceptor_loss	1.0000
7:143339507:CTAGG:C	acceptor_gain	1.0000
7:143339508:TA:T	acceptor_loss	1.0000

AlphaMissense

6430 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:143331315:G:A	G355R	1.000
7:143331315:G:C	G355R	1.000
7:143331315:G:T	G355W	1.000
7:143331316:G:A	G355E	1.000
7:143331562:G:A	G359E	1.000
7:143341946:G:C	G534R	1.000
7:143341947:G:A	G534D	1.000
7:143342019:C:A	P558H	1.000
7:143342019:C:G	P558R	1.000
7:143320756:A:C	S132R	0.999
7:143320758:C:A	S132R	0.999
7:143320758:C:G	S132R	0.999
7:143320768:G:C	D136H	0.999
7:143321454:A:C	S175R	0.999
7:143321456:C:A	S175R	0.999
7:143321456:C:G	S175R	0.999
7:143321720:G:A	G190R	0.999
7:143321720:G:C	G190R	0.999
7:143321721:G:A	G190E	0.999
7:143321727:C:A	P192H	0.999
7:143321737:G:C	K195N	0.999
7:143321737:G:T	K195N	0.999
7:143321797:G:C	K215N	0.999
7:143321797:G:T	K215N	0.999
7:143321808:T:C	L219P	0.999
7:143321825:A:C	S225R	0.999
7:143321827:T:A	S225R	0.999
7:143321827:T:G	S225R	0.999
7:143321840:G:A	G230R	0.999
7:143321840:G:C	G230R	0.999

dbSNP variants (sampled 300 via entrez): RS1000009879 (7:143340250 G>C), RS1000045147 (7:143331941 G>A), RS1000064011 (7:143347349 G>A,T), RS1000199838 (7:143323078 C>T), RS1000218341 (7:143325680 G>A), RS1000537563 (7:143327324 A>C), RS1000905452 (7:143315738 T>G), RS1001098303 (7:143327916 A>G), RS1001314584 (7:143332758 A>G), RS1001388713 (7:143326028 G>A,T), RS1001414300 (7:143341387 T>C), RS1001435174 (7:143327729 A>C,G), RS1001663631 (7:143318340 C>T), RS1001697124 (7:143341017 A>G,T), RS1001727910 (7:143315100 A>G)

Disease associations

OMIM: gene MIM:118425 | disease phenotypes: MIM:160800, MIM:255700, MIM:255300, MIM:170500, MIM:170400, MIM:270400, MIM:619681

GenCC curated gene-disease

Disease	Classification	Inheritance
myotonia congenita, autosomal dominant	Strong	Autosomal dominant
myotonia congenita, autosomal recessive	Strong	Autosomal recessive
Thomsen and Becker disease	Supportive	Autosomal dominant

Mondo (15): myotonia congenita, autosomal dominant (MONDO:0008055), myotonia congenita, autosomal recessive (MONDO:0009715), Batten-Turner congenital myopathy (MONDO:0100468), hyperkalemic periodic paralysis (MONDO:0008224), hypokalemic periodic paralysis, type 1 (MONDO:0042979), migraine disorder (MONDO:0005277), myopathy (MONDO:0005336), cerebral palsy (MONDO:0006497), myocardial infarction (MONDO:0005068), Smith-Lemli-Opitz syndrome (MONDO:0010035), autosomal dominant intermediate Charcot-Marie-Tooth disease (MONDO:0019548), metachromatic leukodystrophy (MONDO:0018868), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), RASopathy (MONDO:0021060), Thomsen and Becker disease (MONDO:0009710)

Orphanet (8): Thomsen and Becker disease (Orphanet:614), Congenital myotonia (Orphanet:206973), Hyperkalemic periodic paralysis (Orphanet:682), Hypokalemic periodic paralysis (Orphanet:681), Smith-Lemli-Opitz syndrome (Orphanet:818), Autosomal dominant intermediate Charcot-Marie-Tooth disease (Orphanet:90114), Metachromatic leukodystrophy (Orphanet:512), RASopathy (Orphanet:536391)

HPO phenotypes

29 total (30 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000707	Abnormality of the nervous system
HP:0001324	Muscle weakness
HP:0002015	Dysphagia
HP:0002312	Clumsiness
HP:0002486	Myotonia
HP:0003198	Myopathy
HP:0003326	Myalgia
HP:0003394	Muscle spasm
HP:0003457	EMG abnormality
HP:0003458	EMG: myopathic abnormalities
HP:0003552	Muscle stiffness
HP:0003621	Juvenile onset
HP:0003712	Skeletal muscle hypertrophy
HP:0003730	EMG: myotonic runs
HP:0003740	Myotonia with warm-up phenomenon
HP:0008872	Feeding difficulties in infancy
HP:0008968	Muscle hypertrophy of the lower extremities
HP:0009063	Progressive distal muscle weakness
HP:0010548	Percussion myotonia
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011675	Arrhythmia
HP:0012899	Handgrip myotonia
HP:0025605	Lid lag on downgaze
HP:0025708	Early young adult onset
HP:0031546	Cardiac conduction abnormality
HP:0100284	EMG: myotonic discharges
HP:0100021	Cerebral palsy

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D002547	Cerebral Palsy	C10.228.140.140.254
D007966	Leukodystrophy, Metachromatic	C10.228.140.163.100.362.550; C10.228.140.163.100.435.825.850.500; C10.228.140.695.625.550; C10.314.400.550; C16.320.565.189.362.550; C16.320.565.189.435.825.850.500; C16.320.565.398.641.803.925.500; C16.320.565.595.554.825.850.500; C18.452.132.100.362.550; C18.452.132.100.435.825.850.500; C18.452.584.563.641.803.925.500; C18.452.648.189.362.550; C18.452.648.189.435.825.850.500; C18.452.648.398.641.803.925.500; C18.452.648.595.554.825.850.500
D008881	Migraine Disorders	C10.228.140.546.399.750
D009203	Myocardial Infarction	C14.280.647.500; C14.907.585.500; C23.550.513.355.750; C23.550.717.489.750
D009224	Myotonia Congenita	C05.651.662.500; C10.574.500.545; C10.668.491.606.500; C16.320.400.540
D020513	Paralysis, Hyperkalemic Periodic	C05.651.701.600; C10.668.491.650.600; C16.320.565.618.711.600; C18.452.648.618.711.600
D019082	Smith-Lemli-Opitz Syndrome	C16.131.077.860; C16.320.565.398.850; C16.320.565.925.875; C18.452.584.500.937; C18.452.584.563.850; C18.452.648.398.850; C18.452.648.925.875

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — ClC family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
NMD670	Inhibition	5.8	pEC50

Binding affinities (BindingDB)

1 measured of 3 human assays (3 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
SR 147778	KI	1000 nM

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-(4-chlorophenoxy)propionic acid	affects activity, decreases activity	3
bisphenol A	affects cotreatment, decreases methylation, decreases expression	2
aristolochic acid I	increases expression	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	increases expression, decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Sodium Selenite	decreases expression	1

Clinical trials (associated diseases)

304 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00174395	PHASE4	COMPLETED	A Trial to Study of the Effects of Eletriptan 40mg on Mild vs Moderate to Severe Pain Intensity of Migraine
NCT00208065	PHASE4	COMPLETED	Evaluation of Histamine, CGRP and VIP as Markers for Activation of Trigeminal and Parasympathetic Nerve Fibers
NCT00210496	PHASE4	COMPLETED	Potential Impact (Benefit) of Preventative Treatment With Topamax on the Effectiveness of Axert in the Acute Treatment of Migraine
NCT00210509	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Almotriptan Versus Placebo in the Treatment of Migraine Headache
NCT00212810	PHASE4	COMPLETED	Evaluation of the Effectiveness of Topiramate in Preventing the Transformation From Episodic Migraine to Chronic Daily Headache.
NCT00212823	PHASE4	COMPLETED	The Effectiveness of Almotriptan Malate (AXERT®) 12.5 Milligrams When Taken at the Onset of Migraine Pain
NCT00216736	PHASE4	COMPLETED	Oral Dexamethasone for Treatment of Migraine
NCT00259636	PHASE4	WITHDRAWN	Zonisamide for Fibromyalgia & Migraine
NCT00259649	PHASE4	COMPLETED	Prospective Survey of Menstrual Migraine & Prevention With Eletriptan
NCT00297375	PHASE4	COMPLETED	A Study Comparing the Effectiveness and Safety of ULTRACET® (Tramadol HCl/Acetaminophen) Versus Placebo for the Treatment of Acute Pain From a Migraine Headache
NCT00335777	PHASE4	COMPLETED	A Research Study Examining Migranal and Skin Sensitivity in Subjects With Migraine
NCT00363506	PHASE4	UNKNOWN	American Migraine Prevention Study
NCT00364806	PHASE4	COMPLETED	Prochlorperazine vs Metoclopramide
NCT00391755	PHASE4	TERMINATED	A Double-Blind Placebo-Controlled Trial of Rozerem in Migraine Headaches
NCT00397254	PHASE4	COMPLETED	Two Rizatriptan Prescribing Portions for Treatment of Migraine
NCT00443352	PHASE4	COMPLETED	A Research Study Examining The Use Of Duloxetine In The Prevention Of Migraine Headache
NCT00449787	PHASE4	COMPLETED	Comparing Naproxen to Sumatriptan for Emergency Headache Patients
NCT00632385	PHASE4	COMPLETED	Efficacy and Safety of Eletriptan for the Treatment of Migraine in Patients Not Satisfied With Rizatriptan Therapy
NCT00634985	PHASE4	COMPLETED	Safety and Efficacy of Eletriptan for the Treatment of Migraine in Subjects Unsuccessfully Treated With Nonsteroidal Anti-inflammatory Drugs
NCT00637286	PHASE4	COMPLETED	ZAP, US. Zomig for Appropriate for Primary Care
NCT00753311	PHASE4	COMPLETED	Rizatriptan in Acute Treatment of Migraine in Patients With Unilateral Trigeminal-autonomic Symptoms.
NCT00792636	PHASE4	COMPLETED	A Study to Determine the Effect of Sumatriptan and Naproxen Sodium Combination Tablet, Sumatriptan Tablet, and Naproxen Sodium Tablet on Blood Pressure When Treating Migraine Headaches That Occur During a 6-month Period
NCT00799045	PHASE4	COMPLETED	Clopidogrel For the Prevention of New Onset Migraine Headache Following Transcatheter Closure of Atrial Septal Defects
NCT00812214	PHASE4	COMPLETED	Treatment of Insomnia in Migraineurs
NCT00846495	PHASE4	COMPLETED	Pilot Study to Compare Frovatriptan vs. Topiramate for Prevention of Migraine
NCT00893737	PHASE4	COMPLETED	Completeness of Response Following Treatment With Treximet™ for Migraine
NCT00910689	PHASE4	COMPLETED	Drug and Non-Drug Treatment Of Severe Migraine
NCT00915473	PHASE4	COMPLETED	Greater Occipital Nerve Block for Migraine Prophylaxis
NCT01016834	PHASE4	COMPLETED	Evaluation of Treatment Satisfaction and Preference for Sumavel DosePro in the Treatment of Migraine
NCT01057160	PHASE4	COMPLETED	Rizatriptan 10 MG RPD in the Treatment of Acute Migraine
NCT01060111	PHASE4	COMPLETED	An Efficacy and Tolerability Study of Topiramate in Participants With Migraine
NCT01071096	PHASE4	COMPLETED	Calcitonin Gene-related Peptide Levels in Chronic Migraine
NCT01071317	PHASE4	COMPLETED	Trial of Comprehensive Migraine Intervention
NCT01090050	PHASE4	COMPLETED	Treximet in the Treatment of Chronic Migraine
NCT01138150	PHASE4	COMPLETED	Ictal and Interictal Inflammatory Markers in Migraine
NCT01211145	PHASE4	COMPLETED	Zomig - Treatment of Acute Migraine Headache in Adolescents
NCT01267864	PHASE4	COMPLETED	Valproate Versus Ketorolac Versus Metoclopramide
NCT01300546	PHASE4	COMPLETED	Treximet Trademark (TM) in the Prevention and Modification of Disease Progression in Migraine
NCT01319825	PHASE4	UNKNOWN	Preventive Treatment of Episodic and Chronic Migraine
NCT01332864	PHASE4	COMPLETED	Effect of Osteopathic Manipulative Treatment for Patients With Chronic Headache