CLCN7
protein-codingchloride voltage-gated channel 7, the group of Chloride voltage-gated channels|Protein phosphatase 1 regulatory subunits
Gene summary
The product of this gene belongs to the CLC chloride channel family of proteins. Chloride channels play important roles in the plasma membrane and in intracellular organelles. This gene encodes chloride channel 7. Defects in this gene are the cause of osteopetrosis autosomal recessive type 4 (OPTB4), also called infantile malignant osteopetrosis type 2 as well as the cause of autosomal dominant osteopetrosis type 2 (OPTA2), also called autosomal dominant Albers-Schonberg disease or marble disease autosoml dominant. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. OPTA2 is the most common form of osteopetrosis, occurring in adolescence or adulthood. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012676
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008156
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008156
Submitter: ClinGen
CLCN7 was first reported in relation to autosomal dominant CLCN7-related osteopetrosis in 2001 (Bénichou et al.: PMID: 11468688). The condition is characterized by increased bone density leading to bone fragility, as well as the "rugger jersey spine" and "bone within bone" on iliac wings, as evident in radiographs. AD CLCN7-related osteopetrosis is associated with reduced penetrance and a milder phenotype than the recessive form. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability and inheritance pattern between disease assertions. Therefore, the following entities have been split into multiple disease entities: autosomal dominant osteopetrosis 2 (OMIM: 166600); autosomal recessive osteopetrosis 4 (OPTB4, OMIM: 611490); and autosomal dominant Hypopigmentation, Organomegaly, and Delayed Myelination and Development (HOD; OMIM: 618541). The split curations for autosomal recessive OPTB4 and autosomal dominant HOD have been curated separately. 12 variants (missense, frameshift) that have been reported in 37 probands in 7 publications (PMIDs: 11468688, 11741829, 21947783, 21962762, 30229577, 30942407, 36051116) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be dominant negative. This gene-disease relationship is also supported by experimental evidence, including mouse models showing increased bone density in mutants (PMIDs: 24185277, 28942122). In summary, there is definitive evidence supporting the relationship between CLCN7 and autosomal dominant osteopetrosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 12/4/23 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0012679
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008156
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012676
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012676
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008156
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0019026
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012676
Submitter: ClinGen
CLCN7 was first reported in relation to autosomal recessive osteopetrosis in 2001 (Kornak et al., PMID: 11207362 & Cleiren et al., PMID: 11741829). Osteopetrosis is characterized by increased bone density, as a consequence of insufficient reabsorption of immature bone. First symptoms include macrocephaly, frontal bossing, skull structural anomalies, choanal stenosis, hydrocephalus, respiration issues, and hypocalcemia. The disease may cause vision and hearing loss, and facial palsy as well. Typical onset of disease is in the first couple of months of life. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive osteopetrosis (OMIM: 611490), autosomal dominant osteopetrosis (OMIM: 166600), and autosomal dominant hypopigmentation, organomegaly, and delayed myelination and development (HOD; OMIM: 618541). HOD lacks a skeletal phenotype, as it is a lysosomal storage disorder. The autosomal recessive osteopetrosis is more severe than the dominant form of osteopetrosis. The split curations for autosomal dominant osteopetrosis and for autosomal dominant HOD will be completed separately. 16 variants (missense, nonsense, large deletion, large insertion, stop loss) that have been reported in at least 10 probands in 6 publications (PMIDs: 11207362, 11741829, 14584882, 19953639, 30942407, 34753502) are included in this curation. The maximum score for genetic evidence (12 pts.) has been exceeded. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (a mouse model, rescue evidence in mice, cell culture models of patient cells, and interaction evidence) (PMIDs: 11207362, 15706348, 16525474, 33905594). The mouse model was upgraded due to highly specific evidence (radiographs; skeletal anomalies, low body weight, and premature death in mutant mice). The protein was shown to interact with OSTM1 (also associated with autosomal recessive osteopetrosis). In summary, there is definitive evidence supporting the relationship between CLCN7 and autosomal recessive osteopetrosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date (9/6/2023; Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0032805
Submitter: ClinGen
*CLCN7* was first reported in relation to “hypopigmentation, organomegaly, and delayed myelination and development” (HOD), an autosomal dominant disorder resulting from *de novo* variants, in 2019 (Nicoli et al, PMID: 31155284). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there are differences in the molecular mechanism, inheritance pattern, and phenotypic variability for the disorders asserted to be caused by variants in *CLCN7*. Therefore, the following disease entities have been split; autosomal dominant hypopigmentation, organomegaly, and delayed myelination and development (HOD; OMIM: 618541), autosomal recessive osteopetrosis (OMIM: 611490), and autosomal dominant osteopetrosis (OMIM: 166600). The osteopetrosis disorders have been curated by the ClinGen Skeletal Disorders GCEP. Six unrelated individuals with HOD have been reported to date and none of them have any evidence of osteopetrosis (Nicoli et al, 2019, PMID: 31155284; Lee et al, 2024, PMID: 39056574; Polovitskaya et al, 2024, PMID: 38838776; ClinVar SCV006099705.1). These individuals have hypopigmentation of the hair and skin, organomegaly, delayed myelination, and motor delay. Histological findings in various tissues are consistent with a lysosomal storage disorder, and pH in the lysosomes of cultured skin fibroblasts was shown to be reduced. Five of these patients have the same variant, p.Tyr715Cys, which was confirmed to be de novo in four of them, while the sixth has another de novo variant, c.854A>C (p.Lys285Thr). The impact of both variants is supported by multiple lines of functional evidence. (Genetic evidence score = 7 points) This gene-disease relationship is supported by experimental evidence including the function of the *CLCN7* gene product (ClC-7), a Cl- /H+ antiporter that localizes to late endosomes and lysosomes and which is involved in ionic homeostasis of those compartments (Lin et al, 2021, PMID: 33495814; Feng et al, 2023, PMID: 37191899). This role is consistent with the histological findings and lysosomal hyperacidification observed in patients. The features of a mouse which is heterozygous for a knock-in variant equivalent to the human p.Tyr715Cys variant closely recapitulate the phenotype of affected human patients (Nicoli et al, 2019, PMID: 31155284). An analysis of different amino acid substitutions of Tyr715, including the variant identified in patients, provides evidence for the role of these variants in the dramatic enlargement of lysosomal compartments (as seen in cells from patients), increased outward currents, reduced degradative capacity of the lysosomes resulting in lysosomal storage, and impaired autophagy (Bose et al, 2023, PMID: 38136669). More evidence is available in the literature but the maximum for experimental evidence (6 points) has been reached. The relationship between CLCN7 and HOD was first classified by the ClinGen Lysosomal Diseases GCEP on December 5, 2023 (SOP Version 10). At that time, the clinical validity was classified as moderate. Following the ClinGen recuration guidance, the General IEM GCEP added four new cases (Lee et al, 2024, PMID: 39056574; Polovitskaya et al, 2024, PMID: 38838776; ClinVar SCV006099705.1) and functional data (PMID: 38136669), resulting in a classification of definitive for the relationship between *CLCN7* and HOD (SOP v11). Importantly, it is not known if any variants other than p.Tyr715Cys or p.Lys285Thr may cause HOD. The classification was approved by the General IEM GCEP on January 9, 2026.
Inheritance Pattern: AD
Disease ID:MONDO:0032805
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0032805
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032805
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008156
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: SD
Disease ID:MONDO:0008156
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012676
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Allergy/Immunology/Infectious; Hematologic; Musculoskeletal
Rationale: In Autosomal recessive osteopetrosis, early diagnosis can allow medical treatment related to calcium homeostasis, including prevention/treatment of hypocalcemic seizures; Transfusions for hematologic manifestations may be necessary; Individuals may benefit from infectious prophylaxis and early and aggressive treatments of infections; HSCT has been described as beneficial; In Autosomal dominant forms of Osteopetrosis, avoidance of high-fracture risk activities can be beneficial, and calcitriol has been reported as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CLCN7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001287.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 15 | 333 | 4 | 352 | ||
| missense | 10 | 41 | 432 | 50 | 533 | |
| nonsense | 9 | 5 | 1 | 15 | ||
| start loss | 1 | 1 | ||||
| frameshift | 14 | 10 | 2 | 26 | ||
| splice donor/acceptor (+/-2bp) | 2 | 20 | 10 | 32 | ||
| Total | 35 | 76 | 461 | 383 | 4 | 959 |
Highest pathogenic variant AF is 0.000014252217
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001278.1 | 25 | MANE Select | |
| Ensembl | ENSP00000372193.4 | 25 | MANE Select | |
| RefSeq | NP_001107803.1 | 24 | Standard | |
| Ensembl | ENSP00000262318.8 | 24 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Stimuli-sensing channels
- Ion channel transport
- Transport of small molecules
Biological Process
- response to pH
- chloride transmembrane transport
Molecular Function
- voltage-gated chloride channel activity
- chloride channel activity
- protein binding
- ATP binding
- antiporter activity
Cellular Component
- nucleoplasm
- lysosomal membrane
- membrane
- integral component of membrane
- cytoplasmic vesicle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000382745
- Coding exons
- 25
- Length
- 30647
- Individuals with no LoFs
- 125715
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 23
- Defined
- 125738
- p
- 0.0000915
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.11 | 358 | 490 | 0.731 | 0.0000349 | 5100 |
| Missense (PolyPhen) | 92 | 179.97 | 0.51121 | 1769 | ||
| Synonymous | -3.06 | 283 | 225 | 1.26 | 0.0000185 | 1649 |
| Loss of Function | 4.66 | 10 | 43.0 | 0.232 | 0.00000224 | 473 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0.00020 | 0.00020 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000099 | 0.000097 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Slowly voltage-gated channel mediating the exchange of chloride ions against protons. Functions as antiporter and contributes to the acidification of the lysosome lumen. {ECO:0000269|PubMed:18449189, ECO:0000269|PubMed:21527911}.;
- Disease
- DISEASE: Osteopetrosis, autosomal dominant 2 (OPTA2) [MIM:166600]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. OPTA2 is the most common form of osteopetrosis, occurring in adolescence or adulthood. It is characterized by sclerosis, predominantly involving the spine, the pelvis and the skull base. {ECO:0000269|PubMed:11741829, ECO:0000269|PubMed:14584882, ECO:0000269|PubMed:19288050, ECO:0000269|PubMed:19953639, ECO:0000269|PubMed:26395888}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Osteopetrosis, autosomal recessive 2 (OPTB2) [MIM:259710]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. {ECO:0000269|PubMed:26395888}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.298
Intolerance Scores
- LoFtool
- 0.0468
- RVIS EVS
- -1.64
- RVIS percentile EVS
- 2.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.835
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |