SURF1
protein-codingSURF1 cytochrome c oxidase assembly factor, the group of Mitochondrial respiratory chain complex assembly factors
Gene summary
This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency. [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 ~4.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between SURF1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of January 14, 2019. 21 articles were reviewed. SURF1 was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1998 (Tiranti et al., PMID 9837813). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 7 probands in 4 publications (PMIDs 9837813, 10443880, 22488715, 27756633). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by the known biochemical function, expression, rescue studies, and animal models. The mechanism for disease is complex IV deficiency. In summary, there is definitive evidence to support the relationship between SURF1 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 14, 2019 (SOP Version 6).
Inheritance Pattern: AR
Disease ID:MONDO:0014733
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014733
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0700250
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0014733
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *SURF1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of October 17, 2024. The *SURF1* gene encodes an assembly factor critical for assembly of complex IV of the mitochondrial respiratory chain. *SURF1* was first reported in relation to autosomal recessive primary mitochondrial disease in 1998 (PMIDs: 9843204, 9837813). While various names have been given to the constellation of features seen in those with *SURF1*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the SURF1 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *SURF1* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on January 14, 2019 (SOP V6), with a final classification of Definitive. This current curation for the association with primary mitochondrial disease includes the cases included in the LSS curation. Evidence supporting the relationship between *SURF1* and autosomal recessive primary mitochondrial disease includes case-level data and experimental data. This curation includes twelve variants identified in ten unrelated probands from five publications (PMIDs: 9837813, 10443880, 22488715, 27756633, 23829769). There are additional cases reported in the medical literature; however, these were not included in this curation as the maximum genetic evidence score was reached. Nonsense, frameshift, splice, and missense variants have been reported. Affected individuals present with variable clinical features including Leigh syndrome spectrum disorder, ataxia, dystonia, dysarthria, seizures, peripheral neuropathy, muscle weakness and/or atrophy, hypertrophic cardiomyopathy, respiratory failure, ophthalmoplegia, optic atrophy, pigmentary retinopathy, failure to thrive, hypertrichosis, and lactic acidosis (for comprehensive cohort characterization, see Wedatilake et al., 2013, PMID: 23829769). Age of onset is typically childhood but onset across the lifetime has been reported. Complex IV deficiency can be seen in muscle and/or skin fibroblasts. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of the SURF1 protein in complex IV assembly, rescue studies (PMID: 10443880), and animal models (fruit fly, PMID: 25164807; pig, PMID: 29601977; zebrafish, PMID: 36795052). In summary, there is definitive evidence to support the relationship between *SURF1* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on October 17, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0700250
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SURF1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003172.4. 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 | 1 | 2 | 180 | 183 | ||
| missense | 7 | 24 | 191 | 9 | 231 | |
| nonsense | 16 | 9 | 25 | |||
| start loss | 3 | 2 | 1 | 6 | ||
| frameshift | 46 | 36 | 1 | 83 | ||
| splice donor/acceptor (+/-2bp) | 17 | 19 | 3 | 39 | ||
| Total | 90 | 90 | 198 | 189 | 0 | 567 |
Highest pathogenic variant AF is 0.00058091665
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003163.1 | 9 | MANE Select | |
| Ensembl | ENSP00000361042.3 | 9 | MANE Select | |
| RefSeq | NP_001267716.1 | 5 | Standard | |
| Ensembl | ENSP00000482067.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| surf1 | Danio rerio | Structure: secondary motor neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Electron Transport Chain
- Type II diabetes mellitus
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
Biological Process
- oxidative phosphorylation
- respiratory chain complex IV assembly
- aerobic respiration
- electron transport chain
- mitochondrial respiratory chain complex IV assembly
Molecular Function
- cytochrome-c oxidase activity
- protein binding
Cellular Component
- mitochondrial respirasome
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371974
- Coding exons
- 9
- Length
- 4943
- Individuals with no LoFs
- 125648
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 100
- Defined
- 125748
- p
- 0.000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.680 | 177 | 153 | 1.15 | 0.00000886 | 1907 |
| Missense (PolyPhen) | 55 | 46.118 | 1.1926 | 553 | ||
| Synonymous | -3.89 | 95 | 57.5 | 1.65 | 0.00000311 | 624 |
| Loss of Function | -0.668 | 18 | 15.2 | 1.19 | 9.21e-7 | 169 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00077 | 0.00074 | rare |
| Latino/Admixed American | 0.00047 | 0.00046 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00050 | 0.00049 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00044 | 0.00043 | rare |
| South Asian | 0.00040 | 0.00039 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. {ECO:0000269|PubMed:24027061, ECO:0000269|PubMed:9843204, ECO:0000305|PubMed:26321642}.;
- Disease
- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:10647889, ECO:0000269|PubMed:10746561, ECO:0000269|PubMed:14564068, ECO:0000269|PubMed:21937992, ECO:0000269|PubMed:22410471, ECO:0000269|PubMed:22488715, ECO:0000269|PubMed:9843204}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 4K (CMT4K) [MIM:616684]: An autosomal recessive, demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4K patients manifest upper and lower limbs involvement. Some affected individuals have nystagmus and late-onset cerebellar ataxia. {ECO:0000269|PubMed:24027061}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.216
Intolerance Scores
- LoFtool
- 0.384
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.91
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.122
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |