ID CLCN1_HUMAN Reviewed; 988 AA. AC P35523; A4D2H5; Q2M202; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 3. DT 27-MAR-2024, entry version 214. DE RecName: Full=Chloride channel protein 1; DE Short=ClC-1; DE AltName: Full=Chloride channel protein, skeletal muscle; GN Name=CLCN1 {ECO:0000312|HGNC:HGNC:2019}; Synonyms=CLC1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT MCAD LEU-480, VARIANT RP GLN-300, CHARACTERIZATION OF VARIANTS MCAD GLU-230 AND LEU-480, RP CHARACTERIZATION OF VARIANT GLN-300, FUNCTION, SUBCELLULAR LOCATION, AND RP SUBUNIT. RX PubMed=8112288; DOI=10.1002/j.1460-2075.1994.tb06315.x; RA Steinmeyer K., Lorenz C., Pusch M., Koch M.C., Jentsch T.J.; RT "Multimeric structure of ClC-1 chloride channel revealed by mutations in RT dominant myotonia congenita (Thomsen)."; RL EMBO J. 13:737-743(1994). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT TRP-118. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 171-988, AND VARIANT MCAR CYS-413. RX PubMed=1379744; DOI=10.1126/science.1379744; RA Koch M.C., Steinmeyer K., Lorenz C., Ricker K., Wolf F., Otto M., Zoll B., RA Lehmann-Horn F., Grzeschik K.-H., Jentsch T.J.; RT "The skeletal muscle chloride channel in dominant and recessive human RT myotonia."; RL Science 257:797-800(1992). RN [5] RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT MCAD GLU-230. RX PubMed=7981750; DOI=10.1038/ng0493-305; RA George A.L. Jr., Crackower M.A., Abdalla J.A., Hudson A.J., Ebers G.C.; RT "Molecular basis of Thomsen's disease (autosomal dominant myotonia RT congenita)."; RL Nat. Genet. 3:305-310(1993). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT MCAD RP GLU-230. RX PubMed=9122265; DOI=10.1073/pnas.94.6.2729; RA Fahlke C., Beck C.L., George A.L. Jr.; RT "A mutation in autosomal dominant myotonia congenita affects pore RT properties of the muscle chloride channel."; RL Proc. Natl. Acad. Sci. U.S.A. 94:2729-2734(1997). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANT MYOTONIA RP LEVIOR ARG-552. RX PubMed=12456816; DOI=10.1113/jphysiol.2002.027037; RA Ryan A., Ruedel R., Kuchenbecker M., Fahlke C.; RT "A novel alteration of muscle chloride channel gating in myotonia levior."; RL J. Physiol. (Lond.) 545:345-354(2002). RN [8] {ECO:0007744|PDB:6COY, ECO:0007744|PDB:6COZ} RP STRUCTURE BY ELECTRON MICROSCOPY (3.36 ANGSTROMS), SUBUNIT, SUBCELLULAR RP LOCATION, TOPOLOGY, AND CATALYTIC ACTIVITY. RX PubMed=29809153; DOI=10.7554/elife.36629; RA Park E., MacKinnon R.; RT "Structure of the CLC-1 chloride channel from Homo sapiens."; RL Elife 7:0-0(2018). RN [9] RP VARIANTS MCAR ILE-327; CYS-413 AND SER-496, CHARACTERIZATION OF VARIANTS RP MCAR ILE-327 AND SER-496, AND FUNCTION. RX PubMed=7951242; DOI=10.1093/hmg/3.6.941; RA Lorenz C., Meyer-Kleine C., Steinmeyer K., Koch M.C., Jentsch T.J.; RT "Genomic organization of the human muscle chloride channel ClC-1 and RT analysis of novel mutations leading to Becker-type myotonia."; RL Hum. Mol. Genet. 3:941-946(1994). RN [10] RP VARIANT MCAR GLY-136. RX PubMed=7981681; DOI=10.1093/hmg/3.7.1123; RA Heine R., George A.L. Jr., Pika U., Deymeer F., Ruedel R., Lehmann-Horn F.; RT "Proof of a non-functional muscle chloride channel in recessive myotonia RT congenita (Becker) by detection of a 4 base pair deletion."; RL Hum. Mol. Genet. 3:1123-1128(1994). RN [11] RP VARIANTS MCAR LEU-167 AND GLN-338, AND VARIANT GLN-300. RX PubMed=7874130; RA George A.L. Jr., Sloan-Brown K., Fenichel G.M., Mitchell G.A., Spiegel R., RA Pascuzzi R.M.; RT "Nonsense and missense mutations of the muscle chloride channel gene in RT patients with myotonia congenita."; RL Hum. Mol. Genet. 3:2071-2072(1994). RN [12] RP VARIANTS MCAR CYS-105; GLY-136; GLY-165; LEU-167; LYS-291; THR-329; RP CYS-413; ARG-482 AND VAL-485, AND VARIANT MCAD GLN-317. RX PubMed=8533761; RA Meyer-Kleine C., Steinmeyer K., Ricker K., Jentsch T.J., Koch M.C.; RT "Spectrum of mutations in the major human skeletal muscle chloride channel RT gene (CLCN1) leading to myotonia."; RL Am. J. Hum. Genet. 57:1325-1334(1995). RN [13] RP VARIANT MCAD MET-290, VARIANT MYOTONIA LEVIOR ARG-552, AND VARIANT TRP-118. RX PubMed=7581380; DOI=10.1093/hmg/4.8.1397; RA Lehmann-Horn F., Mailaender V., Heine R., George A.L. Jr.; RT "Myotonia levior is a chloride channel disorder."; RL Hum. Mol. Genet. 4:1397-1402(1995). RN [14] RP VARIANT MCAD MET-290, VARIANT MCAR LYS-291, CHARACTERIZATION OF VARIANTS RP MCAD MET-290; GLN-317 AND LEU-480, CHARACTERIZATION OF VARIANT MCAR RP LYS-291, CHARACTERIZATION OF VARIANT MYOTONIA LEVIOR ARG-552, AND RP MUTAGENESIS OF ILE-290 AND GLU-291. RX PubMed=8845168; DOI=10.1016/0896-6273(95)90023-3; RA Pusch M., Steinmeyer K., Koch M.C., Jentsch T.J.; RT "Mutations in dominant human myotonia congenita drastically alter the RT voltage dependence of the CIC-1 chloride channel."; RL Neuron 15:1455-1463(1995). RN [15] RP VARIANTS MCAR CYS-150; ARG-200; CYS-261 AND VAL-415. RX PubMed=8571958; RA Mailaender V., Heine R., Deymeer F., Lehmann-Horn F.; RT "Novel muscle chloride channel mutations and their effects on heterozygous RT carriers."; RL Am. J. Hum. Genet. 58:317-324(1996). RN [16] RP VARIANTS MCAD/MCAR LEU-236; GLU-285; ALA-286; SER-307; VAL-485 AND ASN-556, RP CHARACTERIZATION OF VARIANTS MCAD/MCAR LEU-236; GLU-285; ALA-286; SER-307 RP AND ASN-556, AND FUNCTION. RX PubMed=9736777; DOI=10.1093/hmg/7.11.1753; RA Kubisch C., Schmidt-Rose T., Fontaine B., Bretag A.H., Jentsch T.J.; RT "ClC-1 chloride channel mutations in myotonia congenita: variable RT penetrance of mutations shifting the voltage dependence."; RL Hum. Mol. Genet. 7:1753-1760(1998). RN [17] RP VARIANTS MCAR ILE-563 AND LEU-708. RX PubMed=10215406; RX DOI=10.1002/(sici)1098-1004(1998)11:4<331::aid-humu12>3.0.co;2-3; RA Sangiuolo F., Botta A., Mesoraca A., Servidei S., Merlini L., Fratta G., RA Novelli G., Dallapiccola B.; RT "Identification of five new mutations and three novel polymorphisms in the RT muscle chloride channel gene (CLCN1) in 20 Italian patients with dominant RT and recessive myotonia congenita."; RL Hum. Mutat. 11:331-331(1998). RN [18] RP VARIANTS MCAD/MCAR VAL-161; THR-313 AND ASN-556. RX PubMed=9566422; DOI=10.1212/wnl.50.4.1176; RA Plassart-Schiess E., Gervais A., Eymard B., Lagueny A., Pouget J., RA Warter J.-M., Fardeau M., Jentsch T.J., Fontaine B.; RT "Novel muscle chloride channel (CLCN1) mutations in myotonia congenita with RT various modes of inheritance including incomplete dominance and RT penetrance."; RL Neurology 50:1176-1179(1998). RN [19] RP VARIANT MCAR ARG-499, CHARACTERIZATION OF VARIANT MCAR ARG-499, AND RP MUTAGENESIS OF ARG-496; GLY-499 AND GLU-500. RX PubMed=10644771; DOI=10.1074/jbc.275.4.2999; RA Zhang J., Sanguinetti M.C., Kwiecinski H., Ptacek L.J.; RT "Mechanism of inverted activation of ClC-1 channels caused by a novel RT myotonia congenita mutation."; RL J. Biol. Chem. 275:2999-3005(2000). RN [20] RP VARIANT MCAR LEU-932. RX PubMed=11113225; DOI=10.1212/wnl.55.11.1697; RA Nagamitsu S., Matsuura T., Khajavi M., Armstrong R., Gooch C., Harati Y., RA Ashizawa T.; RT "A 'dystrophic' variant of autosomal recessive myotonia congenita caused by RT novel mutations in the CLCN1 gene."; RL Neurology 55:1697-1703(2000). RN [21] RP VARIANTS MCAD VAL-128; LYS-193; SER-307 AND LEU-480, VARIANT MCAR GLU-285, RP AND VARIANTS THR-437 AND ASN-614. RX PubMed=12661046; DOI=10.1002/mus.10347; RA Colding-Joergensen E., DunOe M., Schwartz M., Vissing J.; RT "Decrement of compound muscle action potential is related to mutation type RT in myotonia congenita."; RL Muscle Nerve 27:449-455(2003). RN [22] RP VARIANT [LARGE SCALE ANALYSIS] LYS-548. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [23] RP VARIANT MCAR SER-190. RX PubMed=19697366; DOI=10.1002/mus.21525; RA Shalata A., Furman H., Adir V., Adir N., Hujeirat Y., Shalev S.A., RA Borochowitz Z.U.; RT "Myotonia congenita in a large consanguineous Arab family: insight into the RT clinical spectrum of carriers and double heterozygotes of a novel mutation RT in the chloride channel CLCN1 gene."; RL Muscle Nerve 41:464-469(2010). RN [24] RP VARIANTS MCAR ARG-164; ARG-197; ILE-533; LEU-536; SER-845 AND GLU-947, RP CHARACTERIZATION OF VARIANTS MCAR ARG-164; SER-190; ARG-197 AND SER-845, RP AND FUNCTION. RX PubMed=22521272; DOI=10.1016/j.jns.2012.03.024; RA Ulzi G., Lecchi M., Sansone V., Redaelli E., Corti E., Saccomanno D., RA Pagliarani S., Corti S., Magri F., Raimondi M., D'Angelo G., Modoni A., RA Bresolin N., Meola G., Wanke E., Comi G.P., Lucchiari S.; RT "Myotonia congenita: novel mutations in CLCN1 gene and functional RT characterizations in Italian patients."; RL J. Neurol. Sci. 318:65-71(2012). RN [25] RP VARIANTS MCAR LEU-167; ARG-277; TYR-277 AND THR-527, AND CHARACTERIZATION RP OF VARIANTS MCAR ARG-277 AND TYR-277. RX PubMed=22641783; DOI=10.1113/jphysiol.2012.232785; RA Weinberger S., Wojciechowski D., Sternberg D., Lehmann-Horn F., RA Jurkat-Rott K., Becher T., Begemann B., Fahlke C., Fischer M.; RT "Disease-causing mutations C277R and C277Y modify gating of human ClC-1 RT chloride channels in myotonia congenita."; RL J. Physiol. (Lond.) 590:3449-3464(2012). RN [26] RP VARIANTS MCAD PRO-198 AND LEU-484, CHARACTERIZATION OF VARIANTS MCAD RP PRO-198 AND LEU-484, VARIANTS MCAR PRO-628 AND GLY-640, AND RP CHARACTERIZATION OF VARIANTS MCAR PRO-628 AND GLY-640. RX PubMed=26096614; DOI=10.1113/jp270358; RA Imbrici P., Maggi L., Mangiatordi G.F., Dinardo M.M., Altamura C., RA Brugnoni R., Alberga D., Pinter G.L., Ricci G., Siciliano G., Micheli R., RA Annicchiarico G., Lattanzi G., Nicolotti O., Morandi L., Bernasconi P., RA Desaphy J.F., Mantegazza R., Camerino D.C.; RT "ClC-1 mutations in myotonia congenita patients: insights into molecular RT gating mechanisms and genotype-phenotype correlation."; RL J. Physiol. (Lond.) 593:4181-4199(2015). RN [27] RP VARIANTS MCAR ALA-82; SER-190; VAL-270 AND TRP-453, CHARACTERIZATION OF RP VARIANTS MCAR ALA-82; SER-190; VAL-270 AND TRP-453, AND FUNCTION. RX PubMed=26007199; DOI=10.1007/s12017-015-8356-8; RA Portaro S., Altamura C., Licata N., Camerino G.M., Imbrici P., Musumeci O., RA Rodolico C., Conte Camerino D., Toscano A., Desaphy J.F.; RT "Clinical, molecular, and functional characterization of CLCN1 mutations in RT three families with recessive myotonia congenita."; RL NeuroMolecular Med. 17:285-296(2015). RN [28] RP VARIANTS MCAR ARG-43; LEU-70; ASP-137; HIS-160; SER-496 AND GLU-855, RP CHARACTERIZATION OF VARIANTS MCAR ARG-43; LEU-70; ASP-137 AND HIS-160, RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=26502825; DOI=10.1038/srep15382; RA Ronstedt K., Sternberg D., Detro-Dassen S., Gramkow T., Begemann B., RA Becher T., Kilian P., Grieschat M., Machtens J.P., Schmalzing G., RA Fischer M., Fahlke C.; RT "Impaired surface membrane insertion of homo- and heterodimeric human RT muscle chloride channels carrying amino-terminal myotonia-causing RT mutations."; RL Sci. Rep. 5:15382-15382(2015). RN [29] RP VARIANTS MCAR CYS-105; LEU-167 AND PRO-412, VARIANT ARG-154, RP CHARACTERIZATION OF VARIANTS MCAR CYS-105; LEU-167 AND PRO-412, RP CHARACTERIZATION OF VARIANT ARG-154, AND FUNCTION. RX PubMed=26510092; DOI=10.1002/humu.22916; RA Vindas-Smith R., Fiore M., Vasquez M., Cuenca P., Del Valle G., RA Lagostena L., Gaitan-Penas H., Estevez R., Pusch M., Morales F.; RT "Identification and functional characterization of CLCN1 mutations found in RT nondystrophic myotonia patients."; RL Hum. Mutat. 37:74-83(2016). RN [30] RP VARIANT MCAD LYS-950. RX PubMed=27653901; DOI=10.1016/j.jns.2016.08.030; RA Kato H., Kokunai Y., Dalle C., Kubota T., Madokoro Y., Yuasa H., Uchida Y., RA Ikeda T., Mochizuki H., Nicole S., Fontaine B., Takahashi M.P., Mitake S.; RT "A case of non-dystrophic myotonia with concomitant mutations in the SCN4A RT and CLCN1 genes."; RL J. Neurol. Sci. 369:254-258(2016). RN [31] RP VARIANT MCAD HIS-480, AND CHARACTERIZATION OF VARIANT MCAD HIS-480. RX PubMed=27666773; DOI=10.1016/j.nmd.2016.08.016; RA Mori Y., Yamashita S., Kato M., Masuda T., Takamatsu K., Kumamoto T., RA Sasaki R., Ando Y.; RT "Thomsen disease with ptosis and abnormal MR findings."; RL Neuromuscul. Disord. 26:805-808(2016). CC -!- FUNCTION: Voltage-gated chloride channel (PubMed:8112288, CC PubMed:9122265, PubMed:12456816). Plays an important role in membrane CC repolarization in skeletal muscle cells after muscle contraction. The CC CLC channel family contains both chloride channels and proton-coupled CC anion transporters that exchange chloride or another anion for protons CC (Probable). The absence of conserved gating glutamate residues is CC typical for family members that function as channels (Probable). CC {ECO:0000269|PubMed:12456816, ECO:0000269|PubMed:22521272, CC ECO:0000269|PubMed:26007199, ECO:0000269|PubMed:26502825, CC ECO:0000269|PubMed:26510092, ECO:0000269|PubMed:7951242, CC ECO:0000269|PubMed:8112288, ECO:0000269|PubMed:9122265, CC ECO:0000269|PubMed:9736777, ECO:0000305|PubMed:29809153}. CC -!- CATALYTIC ACTIVITY: CC Reaction=2 chloride(in) + H(+)(out) = 2 chloride(out) + H(+)(in); CC Xref=Rhea:RHEA:29567, ChEBI:CHEBI:15378, ChEBI:CHEBI:17996; CC Evidence={ECO:0000303|PubMed:29809153}; CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:26502825, CC ECO:0000269|PubMed:29809153, ECO:0000305|PubMed:8112288}. CC -!- INTERACTION: CC P35523; Q92624: APPBP2; NbExp=6; IntAct=EBI-10206780, EBI-743771; CC P35523; Q9UHD4: CIDEB; NbExp=3; IntAct=EBI-10206780, EBI-7062247; CC P35523; Q8IZU0: FAM9B; NbExp=3; IntAct=EBI-10206780, EBI-10175124; CC P35523; Q9NQX1-2: PRDM5; NbExp=3; IntAct=EBI-10206780, EBI-12859340; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:12456816, CC ECO:0000269|PubMed:26502825, ECO:0000269|PubMed:8112288, CC ECO:0000269|PubMed:9122265}; Multi-pass membrane protein CC {ECO:0000269|PubMed:29809153}. CC -!- TISSUE SPECIFICITY: Predominantly expressed in skeletal muscles. CC -!- DISEASE: Myotonia congenita, autosomal dominant (MCAD) [MIM:160800]: A CC non-dystrophic skeletal muscle disorder characterized by muscle CC stiffness and an inability of the muscle to relax after voluntary CC contraction. Most patients have symptom onset in the legs, which later CC progresses to the arms, neck, and facial muscles. Many patients show CC marked hypertrophy of the lower limb muscles. The autosomal dominant CC form (Thomsen disease) is less common and less severe than the CC autosomal recessive one (Becker disease). A milder form of autosomal CC dominant myotonia is characterized by isolated myotonia without muscle CC weakness, hypotrophy, or hypertrophy (myotonia levior). CC {ECO:0000269|PubMed:12661046, ECO:0000269|PubMed:26096614, CC ECO:0000269|PubMed:27653901, ECO:0000269|PubMed:27666773, CC ECO:0000269|PubMed:7581380, ECO:0000269|PubMed:7981750, CC ECO:0000269|PubMed:8112288, ECO:0000269|PubMed:8533761, CC ECO:0000269|PubMed:8845168, ECO:0000269|PubMed:9122265, CC ECO:0000269|PubMed:9566422, ECO:0000269|PubMed:9736777}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Myotonia congenita, autosomal recessive (MCAR) [MIM:255700]: A CC non-dystrophic skeletal muscle disorder characterized by muscle CC stiffness and an inability of the muscle to relax after voluntary CC contraction. Most patients have symptom onset in the legs, which later CC progresses to the arms, neck, and facial muscles. Many patients show CC marked hypertrophy of the lower limb muscles. The autosomal recessive CC form (Becker disease) is more severe than the autosomal dominant one CC (Thomsen disease). {ECO:0000269|PubMed:10215406, CC ECO:0000269|PubMed:10644771, ECO:0000269|PubMed:11113225, CC ECO:0000269|PubMed:12661046, ECO:0000269|PubMed:1379744, CC ECO:0000269|PubMed:19697366, ECO:0000269|PubMed:22521272, CC ECO:0000269|PubMed:22641783, ECO:0000269|PubMed:26007199, CC ECO:0000269|PubMed:26096614, ECO:0000269|PubMed:26502825, CC ECO:0000269|PubMed:26510092, ECO:0000269|PubMed:7874130, CC ECO:0000269|PubMed:7951242, ECO:0000269|PubMed:7981681, CC ECO:0000269|PubMed:8533761, ECO:0000269|PubMed:8571958, CC ECO:0000269|PubMed:8845168, ECO:0000269|PubMed:9566422, CC ECO:0000269|PubMed:9736777}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC- CC 1/CLCN1 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Z25587; CAA80996.1; -; Genomic_DNA. DR EMBL; Z25884; CAA81103.1; -; mRNA. DR EMBL; CH236959; EAL23786.1; -; Genomic_DNA. DR EMBL; BC112156; AAI12157.1; -; mRNA. DR EMBL; BC113495; AAI13496.1; -; mRNA. DR EMBL; M97820; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; L08261; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; L08262; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; L08263; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; L08264; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; L08265; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; Z25753; CAB56792.1; -; Genomic_DNA. DR EMBL; Z25754; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25755; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25756; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25757; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25758; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25759; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25760; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25761; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25762; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25763; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25764; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25765; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25766; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25767; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25752; CAB56792.1; JOINED; Genomic_DNA. DR EMBL; Z25768; CAB56814.1; -; Genomic_DNA. DR EMBL; Z25872; CAB56814.1; JOINED; Genomic_DNA. DR CCDS; CCDS5881.1; -. DR PIR; S37078; S37078. DR RefSeq; NP_000074.2; NM_000083.2. DR PDB; 6COY; EM; 3.36 A; A/B=1-988. DR PDB; 6COZ; EM; 3.36 A; A/B=1-988. DR PDB; 6QV6; EM; 3.63 A; A/B=1-988. DR PDB; 6QVB; EM; 4.34 A; A/B=1-988. DR PDB; 6QVC; EM; 4.00 A; A/B=1-988. DR PDB; 6QVD; EM; 4.34 A; A/B=1-988. DR PDB; 6QVU; EM; 4.20 A; A/B=1-988. DR PDBsum; 6COY; -. DR PDBsum; 6COZ; -. DR PDBsum; 6QV6; -. DR PDBsum; 6QVB; -. DR PDBsum; 6QVC; -. DR PDBsum; 6QVD; -. DR PDBsum; 6QVU; -. DR AlphaFoldDB; P35523; -. DR EMDB; EMD-4645; -. DR EMDB; EMD-4646; -. DR EMDB; EMD-4647; -. DR EMDB; EMD-4649; -. DR EMDB; EMD-4657; -. DR EMDB; EMD-7544; -. DR EMDB; EMD-7545; -. DR SMR; P35523; -. DR BioGRID; 107594; 13. DR IntAct; P35523; 6. DR MINT; P35523; -. DR STRING; 9606.ENSP00000339867; -. DR BindingDB; P35523; -. DR TCDB; 2.A.49.2.1; the chloride carrier/channel (clc) family. DR iPTMnet; P35523; -. DR PhosphoSitePlus; P35523; -. DR BioMuta; CLCN1; -. DR DMDM; 311033468; -. DR EPD; P35523; -. DR jPOST; P35523; -. DR MassIVE; P35523; -. DR PaxDb; 9606-ENSP00000339867; -. DR PeptideAtlas; P35523; -. DR ProteomicsDB; 55076; -. DR Antibodypedia; 32627; 168 antibodies from 23 providers. DR DNASU; 1180; -. DR Ensembl; ENST00000343257.7; ENSP00000339867.2; ENSG00000188037.14. DR GeneID; 1180; -. DR KEGG; hsa:1180; -. DR MANE-Select; ENST00000343257.7; ENSP00000339867.2; NM_000083.3; NP_000074.3. DR UCSC; uc003wcr.2; human. DR AGR; HGNC:2019; -. DR CTD; 1180; -. DR DisGeNET; 1180; -. DR GeneCards; CLCN1; -. DR GeneReviews; CLCN1; -. DR HGNC; HGNC:2019; CLCN1. DR HPA; ENSG00000188037; Tissue enriched (skeletal). DR MalaCards; CLCN1; -. DR MIM; 118425; gene. DR MIM; 160800; phenotype. DR MIM; 255700; phenotype. DR neXtProt; NX_P35523; -. DR OpenTargets; ENSG00000188037; -. DR Orphanet; 614; Thomsen and Becker disease. DR PharmGKB; PA26546; -. DR VEuPathDB; HostDB:ENSG00000188037; -. DR eggNOG; KOG0476; Eukaryota. DR GeneTree; ENSGT00940000157383; -. DR HOGENOM; CLU_006904_0_1_1; -. DR InParanoid; P35523; -. DR OMA; QPYYYAD; -. DR OrthoDB; 1194at2759; -. DR PhylomeDB; P35523; -. DR TreeFam; TF352264; -. DR PathwayCommons; P35523; -. DR Reactome; R-HSA-2672351; Stimuli-sensing channels. DR SignaLink; P35523; -. DR BioGRID-ORCS; 1180; 13 hits in 1139 CRISPR screens. DR ChiTaRS; CLCN1; human. DR GeneWiki; CLCN1; -. DR GenomeRNAi; 1180; -. DR Pharos; P35523; Tbio. DR PRO; PR:P35523; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; P35523; Protein. DR Bgee; ENSG00000188037; Expressed in hindlimb stylopod muscle and 94 other cell types or tissues. DR ExpressionAtlas; P35523; baseline and differential. DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0005247; F:voltage-gated chloride channel activity; IMP:UniProtKB. DR GO; GO:1902476; P:chloride transmembrane transport; IMP:UniProtKB. DR GO; GO:0006821; P:chloride transport; IBA:GO_Central. DR GO; GO:0006936; P:muscle contraction; IMP:UniProtKB. DR GO; GO:0019227; P:neuronal action potential propagation; IEA:Ensembl. DR CDD; cd03683; ClC_1_like; 1. DR Gene3D; 3.10.580.10; CBS-domain; 2. DR Gene3D; 1.10.3080.10; Clc chloride channel; 1. DR InterPro; IPR046342; CBS_dom_sf. DR InterPro; IPR014743; Cl-channel_core. DR InterPro; IPR001807; Cl-channel_volt-gated. DR InterPro; IPR002243; Cl_channel-1. DR PANTHER; PTHR45720:SF4; CHLORIDE CHANNEL PROTEIN 1; 1. DR PANTHER; PTHR45720; CHLORIDE CHANNEL PROTEIN 2; 1. DR Pfam; PF00654; Voltage_CLC; 1. DR PRINTS; PR00762; CLCHANNEL. DR PRINTS; PR01112; CLCHANNEL1. DR SUPFAM; SSF54631; CBS-domain pair; 1. DR SUPFAM; SSF81340; Clc chloride channel; 1. DR PROSITE; PS51371; CBS; 2. DR Genevisible; P35523; HS. PE 1: Evidence at protein level; KW 3D-structure; CBS domain; Cell membrane; Chloride; Chloride channel; KW Disease variant; Ion channel; Ion transport; Membrane; Phosphoprotein; KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport; KW Voltage-gated channel. FT CHAIN 1..988 FT /note="Chloride channel protein 1" FT /id="PRO_0000094429" FT TOPO_DOM 1..118 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 119..150 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 151..158 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 159..179 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 180..183 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT INTRAMEM 184..195 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 196..208 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 209..228 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TRANSMEM 229..246 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 247..268 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT INTRAMEM 269..290 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 291..301 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 302..321 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 322..347 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 348..376 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 377..390 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT TRANSMEM 391..408 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 409..414 FT /note="Extracellular" FT /evidence="ECO:0000305" FT INTRAMEM 415..426 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 427..457 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 458..478 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TRANSMEM 479..498 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 499..521 FT /note="Extracellular" FT /evidence="ECO:0000305" FT INTRAMEM 522..554 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 555..557 FT /note="Extracellular" FT /evidence="ECO:0000305" FT TRANSMEM 558..578 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:29809153" FT TOPO_DOM 579..988 FT /note="Cytoplasmic" FT /evidence="ECO:0000305" FT DOMAIN 609..668 FT /note="CBS 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703" FT DOMAIN 821..876 FT /note="CBS 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703" FT REGION 65..92 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 713..764 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 880..988 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 188..192 FT /note="Selectivity filter part_1" FT /evidence="ECO:0000250" FT MOTIF 230..234 FT /note="Selectivity filter part_2" FT /evidence="ECO:0000250" FT MOTIF 482..486 FT /note="Selectivity filter part_3" FT /evidence="ECO:0000250" FT COMPBIAS 883..904 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 189 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /evidence="ECO:0000250|UniProtKB:P37019" FT BINDING 484 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /evidence="ECO:0000250|UniProtKB:P37019" FT BINDING 578 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /evidence="ECO:0000250|UniProtKB:P37019" FT MOD_RES 886 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q64347" FT VARIANT 43 FT /note="Q -> R (in MCAR; decreased chloride transport; FT decreased localization to the plasma membrane; dominant FT negative effect on chloride transport and localization to FT the plasma membrane; no significant effect on chloride FT channel activity; no effect on homodimerization; FT dbSNP:rs868831424)" FT /evidence="ECO:0000269|PubMed:26502825" FT /id="VAR_075588" FT VARIANT 70 FT /note="S -> L (in MCAR; uncertain significance; no effect FT on chloride transport; dbSNP:rs769312894)" FT /evidence="ECO:0000269|PubMed:26502825" FT /id="VAR_075589" FT VARIANT 82 FT /note="T -> A (in MCAR; uncertain significance; no effect FT on chloride transport; dbSNP:rs772100356)" FT /evidence="ECO:0000269|PubMed:26007199" FT /id="VAR_075590" FT VARIANT 105 FT /note="R -> C (in MCAR; no effect on chloride transport; FT dbSNP:rs201509501)" FT /evidence="ECO:0000269|PubMed:26510092, FT ECO:0000269|PubMed:8533761" FT /id="VAR_001582" FT VARIANT 118 FT /note="G -> W (in dbSNP:rs10282312)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:7581380" FT /id="VAR_001583" FT VARIANT 128 FT /note="M -> V (in MCAD; dbSNP:rs80356699)" FT /evidence="ECO:0000269|PubMed:12661046" FT /id="VAR_075591" FT VARIANT 136 FT /note="D -> G (in MCAR)" FT /evidence="ECO:0000269|PubMed:7981681, FT ECO:0000269|PubMed:8533761" FT /id="VAR_001584" FT VARIANT 137 FT /note="Y -> D (in MCAR; reduced chloride transport; FT decreased localization to the plasma membrane; no FT significant effect on chloride channel activity; FT dbSNP:rs748639603)" FT /evidence="ECO:0000269|PubMed:26502825" FT /id="VAR_075592" FT VARIANT 150 FT /note="Y -> C (in MCAR)" FT /evidence="ECO:0000269|PubMed:8571958" FT /id="VAR_001585" FT VARIANT 154 FT /note="Q -> R (no effect on chloride transport; FT dbSNP:rs111482384)" FT /evidence="ECO:0000269|PubMed:26510092" FT /id="VAR_075593" FT VARIANT 160 FT /note="Q -> H (in MCAR; reduced chloride transport; FT decreased localization to the plasma membrane; no FT significant effect on chloride channel activity; FT dbSNP:rs771532474)" FT /evidence="ECO:0000269|PubMed:26502825" FT /id="VAR_075594" FT VARIANT 161 FT /note="F -> V (in MCAD and MCAR)" FT /evidence="ECO:0000269|PubMed:9566422" FT /id="VAR_001586" FT VARIANT 164 FT /note="W -> R (in MCAR; altered chloride channel activity)" FT /evidence="ECO:0000269|PubMed:22521272" FT /id="VAR_075595" FT VARIANT 165 FT /note="V -> G (in MCAR; dbSNP:rs1586485438)" FT /evidence="ECO:0000269|PubMed:8533761" FT /id="VAR_001587" FT VARIANT 167 FT /note="F -> L (in MCAR; no effect on chloride transport; FT dbSNP:rs149729531)" FT /evidence="ECO:0000269|PubMed:22641783, FT ECO:0000269|PubMed:26510092, ECO:0000269|PubMed:7874130, FT ECO:0000269|PubMed:8533761" FT /id="VAR_001588" FT VARIANT 190 FT /note="G -> S (in MCAR; loss of chloride channel activity; FT dbSNP:rs797045032)" FT /evidence="ECO:0000269|PubMed:19697366, FT ECO:0000269|PubMed:22521272, ECO:0000269|PubMed:26007199" FT /id="VAR_075596" FT VARIANT 193 FT /note="E -> K (in MCAD; dbSNP:rs80356686)" FT /evidence="ECO:0000269|PubMed:12661046" FT /id="VAR_075597" FT VARIANT 197 FT /note="I -> R (in MCAR; changed chloride channel activity)" FT /evidence="ECO:0000269|PubMed:22521272" FT /id="VAR_075598" FT VARIANT 198 FT /note="L -> P (in MCAD; reduced chloride transport; changed FT calcium channel activity; changed gating of the channel; FT dbSNP:rs1347382107)" FT /evidence="ECO:0000269|PubMed:26096614" FT /id="VAR_075599" FT VARIANT 200 FT /note="G -> R (in MCAD and MCAR; dbSNP:rs1563074523)" FT /evidence="ECO:0000269|PubMed:8571958" FT /id="VAR_001589" FT VARIANT 230 FT /note="G -> E (in MCAD and MCAR; changed ion selectivity; FT loss of chloride transport; mild dominant effect; FT dbSNP:rs80356700)" FT /evidence="ECO:0000269|PubMed:7981750, FT ECO:0000269|PubMed:8112288, ECO:0000269|PubMed:9122265" FT /id="VAR_001590" FT VARIANT 236 FT /note="V -> L (in MCAR; loss of chloride transport; changed FT calcium channel activity; changed gating of the channel; FT dbSNP:rs776173406)" FT /evidence="ECO:0000269|PubMed:9736777" FT /id="VAR_001591" FT VARIANT 261 FT /note="Y -> C (in MCAR; dbSNP:rs200621976)" FT /evidence="ECO:0000269|PubMed:8571958" FT /id="VAR_001592" FT VARIANT 270 FT /note="G -> V (in MCAR; decreased chloride channel FT activity)" FT /evidence="ECO:0000269|PubMed:26007199" FT /id="VAR_075600" FT VARIANT 277 FT /note="C -> R (in MCAR; reduced chloride transport; no FT effect on protein abundance; dbSNP:rs757109632)" FT /evidence="ECO:0000269|PubMed:22641783" FT /id="VAR_075601" FT VARIANT 277 FT /note="C -> Y (in MCAR; reduced chloride transport; changed FT calcium channel activity; changed gating of the channel; no FT effect on protein abundance)" FT /evidence="ECO:0000269|PubMed:22641783" FT /id="VAR_075602" FT VARIANT 285 FT /note="G -> E (in MCAR; loss of chloride channel activity; FT dbSNP:rs150885084)" FT /evidence="ECO:0000269|PubMed:12661046, FT ECO:0000269|PubMed:9736777" FT /id="VAR_001593" FT VARIANT 286 FT /note="V -> A (in MCAD; reduced chloride transport; changed FT calcium channel activity; changed gating of the channel; FT dominant negative effect; dbSNP:rs80356689)" FT /evidence="ECO:0000269|PubMed:9736777" FT /id="VAR_001594" FT VARIANT 290 FT /note="I -> M (in MCAD; reduced chloride transport; changed FT chloride channel activity; changed gating of the channel; FT dominant negative effect; dbSNP:rs80356690)" FT /evidence="ECO:0000269|PubMed:7581380, FT ECO:0000269|PubMed:8845168" FT /id="VAR_001595" FT VARIANT 291 FT /note="E -> K (in MCAR; loss of calcium channel activity; FT no dominant negative effect; dbSNP:rs121912805)" FT /evidence="ECO:0000269|PubMed:8533761, FT ECO:0000269|PubMed:8845168" FT /id="VAR_001596" FT VARIANT 300 FT /note="R -> Q (no effect on chloride transport; FT dbSNP:rs118066140)" FT /evidence="ECO:0000269|PubMed:7874130, FT ECO:0000269|PubMed:8112288" FT /id="VAR_001597" FT VARIANT 307 FT /note="F -> S (in MCAD; reduced chloride transport; changed FT chloride channel activity; changed gating of the channel; FT dominant negative effect; dbSNP:rs80356701)" FT /evidence="ECO:0000269|PubMed:12661046, FT ECO:0000269|PubMed:9736777" FT /id="VAR_001598" FT VARIANT 313 FT /note="A -> T (in MCAD and MCAR; dbSNP:rs80356692)" FT /evidence="ECO:0000269|PubMed:9566422" FT /id="VAR_001599" FT VARIANT 317 FT /note="R -> Q (in MCAD; reduced chloride transport; changed FT chloride channel activity; changed gating of the channel; FT dbSNP:rs80356702)" FT /evidence="ECO:0000269|PubMed:8533761, FT ECO:0000269|PubMed:8845168" FT /id="VAR_001600" FT VARIANT 327 FT /note="V -> I (in MCAR; due to a nucleotide substitution FT that can affect splicing or results in missense variant FT I-327; the missense variant does not affect chloride FT channel activity when expressed in Xenopus oocytes; FT dbSNP:rs774396430)" FT /evidence="ECO:0000269|PubMed:7951242" FT /id="VAR_001601" FT VARIANT 329 FT /note="I -> T (in MCAR)" FT /evidence="ECO:0000269|PubMed:8533761" FT /id="VAR_001602" FT VARIANT 338 FT /note="R -> Q (in MCAD and MCAR; dbSNP:rs80356703)" FT /evidence="ECO:0000269|PubMed:7874130" FT /id="VAR_001603" FT VARIANT 412 FT /note="Q -> P (in MCAR; loss of chloride transport; FT decreased localization to the plasma membrane; loss of FT homodimerization; might be degraded; dbSNP:rs1279658001)" FT /evidence="ECO:0000269|PubMed:26510092" FT /id="VAR_075603" FT VARIANT 413 FT /note="F -> C (in MCAR; dbSNP:rs121912799)" FT /evidence="ECO:0000269|PubMed:1379744, FT ECO:0000269|PubMed:7951242, ECO:0000269|PubMed:8533761" FT /id="VAR_001604" FT VARIANT 415 FT /note="A -> V (in MCAR)" FT /evidence="ECO:0000269|PubMed:8571958" FT /id="VAR_001605" FT VARIANT 437 FT /note="A -> T (in dbSNP:rs41276054)" FT /evidence="ECO:0000269|PubMed:12661046" FT /id="VAR_001606" FT VARIANT 453 FT /note="R -> W (in MCAR; uncertain significance; no effect FT on chloride channel activity; dbSNP:rs376026619)" FT /evidence="ECO:0000269|PubMed:26007199" FT /id="VAR_075604" FT VARIANT 480 FT /note="P -> H (in MCAD; decreased protein abundance)" FT /evidence="ECO:0000269|PubMed:27666773" FT /id="VAR_077244" FT VARIANT 480 FT /note="P -> L (in MCAD; loss of chloride transport; changed FT chloride channel activity; changed gating of the channel; FT dominant effect; dbSNP:rs80356694)" FT /evidence="ECO:0000269|PubMed:12661046, FT ECO:0000269|PubMed:8112288, ECO:0000269|PubMed:8845168" FT /id="VAR_001607" FT VARIANT 482 FT /note="G -> R (in MCAR; dbSNP:rs746125212)" FT /evidence="ECO:0000269|PubMed:8533761" FT /id="VAR_001608" FT VARIANT 484 FT /note="F -> L (in MCAD; reduced chloride transport; changed FT calcium channel activity; changed channel gating; no FT dominant negative effect; dbSNP:rs1312002847)" FT /evidence="ECO:0000269|PubMed:26096614" FT /id="VAR_075605" FT VARIANT 485 FT /note="M -> V (in MCAR; dbSNP:rs146457619)" FT /evidence="ECO:0000269|PubMed:8533761, FT ECO:0000269|PubMed:9736777" FT /id="VAR_001609" FT VARIANT 496 FT /note="R -> S (in MCAR; loss of chloride channel activity; FT recessive; dbSNP:rs121912801)" FT /evidence="ECO:0000269|PubMed:26502825, FT ECO:0000269|PubMed:7951242" FT /id="VAR_001610" FT VARIANT 499 FT /note="G -> R (in MCAR; reduced chloride transport; changed FT calcium channel activity; changed channel gating; FT dbSNP:rs121912807)" FT /evidence="ECO:0000269|PubMed:10644771" FT /id="VAR_075606" FT VARIANT 527 FT /note="I -> T (in MCAR; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22641783" FT /id="VAR_075607" FT VARIANT 533 FT /note="T -> I (in MCAR; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22521272" FT /id="VAR_075608" FT VARIANT 536 FT /note="V -> L (in MCAR; uncertain significance; FT dbSNP:rs777685454)" FT /evidence="ECO:0000269|PubMed:22521272" FT /id="VAR_075609" FT VARIANT 548 FT /note="E -> K (in a breast cancer sample; somatic mutation; FT dbSNP:rs546411827)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036300" FT VARIANT 552 FT /note="Q -> R (in MCAD and MCAR; also found in myotonia FT levior; reduced chloride transport; changed calcium channel FT activity; changed channel gating; weak dominant negative FT effect; dbSNP:rs80356696)" FT /evidence="ECO:0000269|PubMed:12456816, FT ECO:0000269|PubMed:7581380, ECO:0000269|PubMed:8845168" FT /id="VAR_001611" FT VARIANT 556 FT /note="I -> N (in MCAD and MCAR; mild form; reduced FT chloride transport; changed chloride channel activity; FT changed gating of the channel; partial dominant negative FT effect; dbSNP:rs80356697)" FT /evidence="ECO:0000269|PubMed:9566422, FT ECO:0000269|PubMed:9736777" FT /id="VAR_001612" FT VARIANT 563 FT /note="V -> I (in MCAR)" FT /evidence="ECO:0000269|PubMed:10215406" FT /id="VAR_001613" FT VARIANT 614 FT /note="K -> N (in dbSNP:rs140205115)" FT /evidence="ECO:0000269|PubMed:12661046" FT /id="VAR_075610" FT VARIANT 628 FT /note="L -> P (in MCAR; uncertain significance; no effect FT on calcium channel activity)" FT /evidence="ECO:0000269|PubMed:26096614" FT /id="VAR_075611" FT VARIANT 640 FT /note="V -> G (in MCAR; reduced calcium channel activity; FT dbSNP:rs1803111906)" FT /evidence="ECO:0000269|PubMed:26096614" FT /id="VAR_075612" FT VARIANT 708 FT /note="F -> L (in MCAR)" FT /evidence="ECO:0000269|PubMed:10215406" FT /id="VAR_001614" FT VARIANT 727 FT /note="P -> L (in dbSNP:rs13438232)" FT /id="VAR_047779" FT VARIANT 845 FT /note="G -> S (in MCAR; uncertain significance; no effect FT on chloride channel activity; dbSNP:rs755433272)" FT /evidence="ECO:0000269|PubMed:22521272" FT /id="VAR_075613" FT VARIANT 855 FT /note="G -> E (in MCAR; uncertain significance; FT dbSNP:rs1554439879)" FT /evidence="ECO:0000269|PubMed:26502825" FT /id="VAR_075614" FT VARIANT 932 FT /note="P -> L (in MCAR; uncertain significance; FT dbSNP:rs80356706)" FT /evidence="ECO:0000269|PubMed:11113225" FT /id="VAR_075615" FT VARIANT 947 FT /note="V -> E (in MCAR; uncertain significance)" FT /evidence="ECO:0000269|PubMed:22521272" FT /id="VAR_075616" FT VARIANT 950 FT /note="E -> K (in MCAD; uncertain significance; FT dbSNP:rs201506176)" FT /evidence="ECO:0000269|PubMed:27653901" FT /id="VAR_079520" FT MUTAGEN 290 FT /note="I->C,E,F,G,K,L,Q,T,V,Y: Changed chloride channel FT activity; changed gating of the channel." FT /evidence="ECO:0000269|PubMed:8845168" FT MUTAGEN 291 FT /note="E->D: No effect on calcium channel activity." FT /evidence="ECO:0000269|PubMed:8845168" FT MUTAGEN 291 FT /note="E->L: Loss of calcium channel activity." FT /evidence="ECO:0000269|PubMed:8845168" FT MUTAGEN 496 FT /note="R->K: Changed gating of the channel." FT /evidence="ECO:0000269|PubMed:10644771" FT MUTAGEN 499 FT /note="G->K,E: Changed gating of the channel." FT /evidence="ECO:0000269|PubMed:10644771" FT MUTAGEN 499 FT /note="G->Q: No effect on gating of the channel." FT /evidence="ECO:0000269|PubMed:10644771" FT MUTAGEN 500 FT /note="E->Q: No effect on channel function." FT /evidence="ECO:0000269|PubMed:10644771" FT CONFLICT 697 FT /note="L -> P (in Ref. 1; CAA80996/CAA81103)" FT /evidence="ECO:0000305" FT HELIX 117..151 FT /evidence="ECO:0007829|PDB:6COY" FT TURN 152..155 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 157..182 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 184..186 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 191..198 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 204..206 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 209..223 FT /evidence="ECO:0007829|PDB:6COY" FT TURN 224..226 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 232..249 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 263..279 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 282..291 FT /evidence="ECO:0007829|PDB:6COY" FT STRAND 293..298 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 299..322 FT /evidence="ECO:0007829|PDB:6COY" FT STRAND 325..329 FT /evidence="ECO:0007829|PDB:6COY" FT STRAND 339..341 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 345..347 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 348..378 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 382..388 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 392..405 FT /evidence="ECO:0007829|PDB:6COY" FT TURN 407..410 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 411..413 FT /evidence="ECO:0007829|PDB:6COY" FT TURN 414..417 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 420..427 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 433..435 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 440..449 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 456..474 FT /evidence="ECO:0007829|PDB:6COY" FT STRAND 477..480 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 484..502 FT /evidence="ECO:0007829|PDB:6COY" FT TURN 503..505 FT /evidence="ECO:0007829|PDB:6COY" FT STRAND 510..512 FT /evidence="ECO:0007829|PDB:6COY" FT STRAND 515..517 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 522..537 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 542..550 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 556..570 FT /evidence="ECO:0007829|PDB:6COY" FT TURN 571..573 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 577..584 FT /evidence="ECO:0007829|PDB:6COY" FT HELIX 605..608 FT /evidence="ECO:0007829|PDB:6COZ" FT STRAND 609..611 FT /evidence="ECO:0007829|PDB:6COZ" FT HELIX 622..631 FT /evidence="ECO:0007829|PDB:6COZ" FT STRAND 635..641 FT /evidence="ECO:0007829|PDB:6COZ" FT TURN 643..645 FT /evidence="ECO:0007829|PDB:6COZ" FT STRAND 647..653 FT /evidence="ECO:0007829|PDB:6COZ" FT HELIX 654..665 FT /evidence="ECO:0007829|PDB:6COZ" FT HELIX 799..810 FT /evidence="ECO:0007829|PDB:6COZ" FT HELIX 834..843 FT /evidence="ECO:0007829|PDB:6COZ" FT STRAND 851..853 FT /evidence="ECO:0007829|PDB:6COZ" FT STRAND 856..860 FT /evidence="ECO:0007829|PDB:6COZ" FT HELIX 863..875 FT /evidence="ECO:0007829|PDB:6COZ" SQ SEQUENCE 988 AA; 108626 MW; CA838BCD2AF3CA68 CRC64; MEQSRSQQRG GEQSWWGSDP QYQYMPFEHC TSYGLPSENG GLQHRLRKDA GPRHNVHPTQ IYGHHKEQFS DREQDIGMPK KTGSSSTVDS KDEDHYSKCQ DCIHRLGQVV RRKLGEDGIF LVLLGLLMAL VSWSMDYVSA KSLQAYKWSY AQMQPSLPLQ FLVWVTFPLV LILFSALFCH LISPQAVGSG IPEMKTILRG VVLKEYLTMK AFVAKVVALT AGLGSGIPVG KEGPFVHIAS ICAAVLSKFM SVFCGVYEQP YYYSDILTVG CAVGVGCCFG TPLGGVLFSI EVTSTYFAVR NYWRGFFAAT FSAFVFRVLA VWNKDAVTIT ALFRTNFRMD FPFDLKELPA FAAIGICCGL LGAVFVYLHR QVMLGVRKHK ALSQFLAKHR LLYPGIVTFV IASFTFPPGM GQFMAGELMP REAISTLFDN NTWVKHAGDP ESLGQSAVWI HPRVNVVIII FLFFVMKFWM SIVATTMPIP CGGFMPVFVL GAAFGRLVGE IMAMLFPDGI LFDDIIYKIL PGGYAVIGAA ALTGAVSHTV STAVICFELT GQIAHILPMM VAVILANMVA QSLQPSLYDS IIQVKKLPYL PDLGWNQLSK YTIFVEDIMV RDVKFVSASY TYGELRTLLQ TTTVKTLPLV DSKDSMILLG SVERSELQAL LQRHLCPERR LRAAQEMARK LSELPYDGKA RLAGEGLPGA PPGRPESFAF VDEDEDEDLS GKSELPPSLA LHPSTTAPLS PEEPNGPLPG HKQQPEAPEP AGQRPSIFQS LLHCLLGRAR PTKKKTTQDS TDLVDNMSPE EIEAWEQEQL SQPVCFDSCC IDQSPFQLVE QTTLHKTHTL FSLLGLHLAY VTSMGKLRGV LALEELQKAI EGHTKSGVQL RPPLASFRNT TSTRKSTGAP PSSAENWNLP EDRPGATGTG DVIAASPETP VPSPSPEPPL SLAPGKVEGE LEELELVESP GLEEELADIL QGPSLRSTDE EDEDELIL //