CHCHD10
protein-codingcoiled-coil-helix-coiled-coil-helix domain containing 10, the group of Coiled-coil-helix-coiled-coil-helix domain containing proteins
Gene summary
This gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. It may play a role in cristae morphology maintenance or oxidative phosphorylation. Mutations in this gene cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 7 and 19. [provided by RefSeq, Aug 2014]
- C22orf16
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017161
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014025
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014532
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014025
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014395
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014395
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014532
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *CHCHD10* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 18, 2023. *CHCHD10* encodes a small protein called coiled-coil-helix-coiled-coil-helix domain containing 10 that localizes to the mitochondrial intermembrane space. While the exact mechanism of disease has not been fully elucidated, it appears that it is involved in mitochondrial genome stability and maintenance of cristae junctions. Defects of this protein are associated with mitochondrial fragmentation and/or trigger the mitochondrial integrated stress response. *CHCHD10* was first reported in relation to autosomal dominant primary mitochondrial disease in 2014 (PMID: 24934289), in two adults with late onset motor neuron disease characterized by dysphagia, dysarthria, areflexia, myopathy and cognitive impairment. While various names have been given to the constellation of features seen in those with *CHCHD10*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *CHCHD10* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique missense variants identified in seven probands from six publications (PMIDs: 25428574, 25833818, 25113787, 35700042, 25193783, 24934289). Of note, toxic gain-of-function appears to be the disease mechanism for the p.Ser59Leu and p.Gly58Arg variants and loss-of-function appears to be the disease mechanism for other variants such as the p.Arg15Leu (PMID: 36158221). Affected individuals have a broad spectrum of features including mitochondrial myopathy with or without cardiomyopathy, motor neuron disease, Charcot Marie Tooth-like phenotypes, and spinal muscular atrophy. While the evidence for primary mitochondrial pathology is less clear in some of these cases, this Expert Panel agreed that these clinical phenotypes are within the spectrum of primary mitochondrial disease and opted to include them in this curation with conservative scoring. Familial segregation was also included in this curation (PMID: 25193783). This gene-disease association is also supported by its known biochemical function and numerous knock-in mouse models of different variants (PMIDs: 30877432, 35700042). Of note, not all animal model *CHCHD10* knockouts display a phenotype (PMID: 29112723). In summary, there is definitive evidence to support the relationship between *CHCHD10* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 18, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014025
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014532
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014395
Submitter: ClinGen
CHCHD10 codes for the coiled-coil-helix-coiled-coil-helix domain containing 10 protein, a mitochondrial protein that is involved in oxidative phosphorylation and cristae morphology maintenance. CHCHD10 has been reported to cause ALS-FTD, mitochondrial myopathy, and late onset spinal muscular atrophy (Jokela type). Mitochondrial myopathy was determined to be an independent disease entity and was spilt from the CHCHD10 curation; however, evidence related to ALS, ALS/FTD, FTD, and late onset spinal muscular atrophy were considered. CHCHD10 was first reported to be responsible for autosomal dominant ALS-FTD in a large, five-generation family of French ancestry through exome sequencing and segregation analysis within the family. At least 17 variants in the CHCHD10 gene have since been reported to cause ALS-FTD in humans of diverse geoancestry across several publications (PMID: 24934289, 25726362, 25113787, 25261972, 25576308, 25155093, 25681414, 25833818, 26152333, 29789341, 26719383, 27056076). However, several reported variants have relatively high minor allele frequencies in population databases (>0.000005 in gnomAD) and were not scored as genetic-level evidence. Notably, the R15L variant in CHCHD10 was consistently reported to cause ALS-FTD across several populations and has functional evidence to support its disruption of mitochondrial function (PMID: 29121267). There is one variant in CHCHD10 that has been reported to cause late onset spinal muscular atrophy (Jokela type) in several families of Finnish ancestry (Gly66Val). This variant was not scored due to high frequency in population databases in the European Finnish population specifically (0.0001891 in gnomAD) (PMID: 21715705, 27810918). Overall evidence supporting the CHCHD10 gene-disease relationship includes case-level data and experimental data. Postmortem analysis of a patient with CHCHD10 ALS (R15L) identified numerous aggregates of CHCHD10 within the anterior horns (PMID: 32042922). A knock-in mouse study (R15L) demonstrated that mutant mice develop progressive motor deficits, abnormal morphology and innervation of the neuromuscular junction, and accelerated mortality (PMID: 30877432). Protein interaction studies have demonstrated that CHCHD10 mutations induce cytoplasmic TDP-43 mis localization, potentiate TDP-43-induced apoptosis and synaptic impairment, and induce insoluble TDP-43 and (PMID: 28585542, 33772006). In summary, there is moderate evidence to support a gene-disease relationship between CHCHD10 and frontotemporal dementia and/or amyotrophic lateral sclerosis 2. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen ALS GCEP on the meeting date September 13, 2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: Cardiovascular; Musculoskeletal
Rationale: Individuals have been described with cardiomyopathy, and awareness may allow medical management; Heart transplant has been described; The condition may manifest with muscle weakness, and medical management (with steroids) has been reported as beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CHCHD10 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_213720.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 53 | 55 | |||
| missense | 3 | 2 | 115 | 12 | 2 | 134 |
| nonsense | 1 | 7 | 8 | |||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 3 | 3 | 132 | 65 | 2 | 205 |
Highest pathogenic variant AF is 0.0029087022
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_998885.1 | 4 | MANE Select | |
| Ensembl | ENSP00000418428.3 | 4 | MANE Select | |
| RefSeq | NP_001288268.1 | 4 | Standard | |
| Ensembl | ENSP00000384973.3 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Metabolism of proteins
- Mitochondrial protein import
Biological Process
- oxidative phosphorylation
- mitochondrion organization
- stabilization of membrane potential
- protein-containing complex disassembly
- protein localization to nucleus
Molecular Function
- molecular_function
- protein binding
Cellular Component
- nucleus
- mitochondrion
- mitochondrial intermembrane space
- MICOS complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000484558
- Coding exons
- 4
- Length
- 2610
- Individuals with no LoFs
- 125343
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 125365
- p
- 0.0000877
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.825 | 47 | 65.8 | 0.714 | 0.00000309 | 842 |
| Missense (PolyPhen) | 22 | 27.018 | 0.81429 | 322 | ||
| Synonymous | -0.414 | 34 | 31.1 | 1.09 | 0.00000164 | 303 |
| Loss of Function | -0.746 | 7 | 5.17 | 1.35 | 2.22e-7 | 59 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00075 | 0.00074 | rare |
| Latino/Admixed American | 0.00018 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000020 | 0.000018 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure. {ECO:0000269|PubMed:24934289}.;
- Disease
- DISEASE: Spinal muscular atrophy, Jokela type (SMAJ) [MIM:615048]: An autosomal dominant, slowly progressive, lower motor neuron disease. SMAJ is characterized by adult-onset of muscle cramps and fasciculations affecting the proximal and distal muscles of the upper and lower limbs. The disorder results in weakness and mild muscle atrophy later in life. {ECO:0000269|PubMed:25428574}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, isolated mitochondrial, autosomal dominant (IMMD) [MIM:616209]: A mitochondrial myopathy presenting with severe exercise intolerance, progressive proximal weakness, and lactic acidemia. The disorder is slowly progressive, with later involvement of facial muscles, muscles of the upper limbs, and distal muscles. {ECO:0000269|PubMed:25193783}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0876
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |