LIPT2
protein-codinglipoyl(octanoyl) transferase 2
Gene summary
This gene encodes a mitochondrial protein that catalyzes the transfer of octanoic acid to lipoate-dependent enzymes such as octanoyl-ACP. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0060562
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0060562
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0060562
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0014576
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0060562
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *LIPT2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 29, 2024. *LIPT2* encodes lipoyl(octanoyl) transferase 2, an enzyme important for lipoic acid biosynthesis. The first and only report of variants in *LIPT2* being associated with autosomal recessive primary mitochondrial disease was in 2017 (PMID: 28757203). While various names have been given to the constellation of features seen in those with *LIPT2*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the LIPT2 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 three missense variants in two probands from one publication (PMID: 28757203). Clinical features in affected individuals include severely delayed to absent psychomotor development, microcephaly, epilepsy, dystonia, spastic tetraparesis, and respiratory distress. Brain imaging showed cortical atrophy, leukodystrophy, delayed myelination, progressive thalamus and putamen abnormalities, and decreased gyrification of the cerebral hemispheres. Pyruvate dehydrogenase complex activity was reduced in skin fibroblasts. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of LIPT2 in lipoic acid biosynthesis and functional studies in patient cells (PMID: 28803783). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 29, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0060562
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Biochemical; 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 LIPT2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001144869.3. 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 | 1 | 25 | 1 | 27 | ||
| missense | 3 | 89 | 4 | 1 | 97 | |
| nonsense | 0 | |||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 4 | 93 | 29 | 2 | 128 |
Highest pathogenic variant AF is 0.0002999843
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001138341.1 | 2 | MANE Select | |
| Ensembl | ENSP00000309463.4 | 2 | MANE Select | |
| RefSeq | NP_001316870.1 | 2 | Standard | |
| RefSeq | NP_001316871.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lipoic acid metabolism - Homo sapiens (human)
- Metabolism of amino acids and derivatives
- Metabolism
- Glyoxylate metabolism and glycine degradation
Biological Process
- protein lipoylation
- cellular nitrogen compound metabolic process
- positive regulation of oxygen metabolic process
Molecular Function
- ligase activity
- lipoyl(octanoyl) transferase activity
- octanoyl transferase activity (acting on glycine-cleavage complex H protein)
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000310109
- Coding exons
- 2
- Length
- 2022
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.120 | 85 | 81.9 | 1.04 | 0.00000446 | 1385 |
| Missense (PolyPhen) | 18 | 26.941 | 0.66813 | 422 | ||
| Synonymous | 0.0827 | 38 | 38.7 | 0.983 | 0.00000237 | 530 |
| Loss of Function | 1.64 | 0 | 3.13 | 0.00 | 1.34e-7 | 62 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the transfer of endogenously produced octanoic acid from octanoyl-acyl-carrier-protein onto the lipoyl domains of lipoate-dependent enzymes, which catalyze essential redox reactions (PubMed:28757203). Lipoyl-ACP can also act as a substrate although octanoyl-ACP is likely to be the physiological substrate (By similarity). {ECO:0000250, ECO:0000269|PubMed:28757203}.;
- Disease
- DISEASE: Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (NELABA) [MIM:617668]: An autosomal recessive disorder characterized by severe encephalopathy with neonatal onset, metabolic features including lactic acidosis, little or no psychomotor development, and brain abnormalities including cerebral atrophy, cysts, and white matter abnormalities. {ECO:0000269|PubMed:28757203}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.813
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |