LYRM7
protein-codingLYR motif containing 7, the group of Mitochondrial respiratory chain complex assembly factors|LYR motif containing
Gene summary
Inner mitochondrial membrane complex III (CIII) is the main enzyme complex in the mitochondrial respiratory chain, and Rieske Fe-S protein (UQCRFS1) is the last catalytic subunit added to the complex. The protein encoded by this gene is a nuclear-encoded mitochondrial matrix protein that stabilizes UQCRFS1 and chaperones it to the CIII complex. Defects in this gene are a cause of mitochondrial complex III deficiency, nuclear type 8. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]
- C5orf31
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~34.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014364
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015448
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *LYRM7* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. The *LYRM7* gene encodes LYR motif containing 7, which is a chaperone protein involved in the assembly of mitochondrial complex III. Defects of this protein lead to complex III deficiency. The *LYRM7 *gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 24014394). While various names have been given to the constellation of features seen in those with *LYRM7*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the LYRM7 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 six unique variants (one missense, one in-frame duplication, one splice region, one canonical splice site, one frameshift, and one stop-gained variant, each identified in a homozygous state) identified in seven unrelated individuals from two publications (PMIDs: 24014394, 26912632). More evidence is available in the literature (e.g., PMIDs: 28694194, 33189022, 33662890), but the maximum score for genetic evidence (12 pts.) has been reached. Features in affected individuals included leukoencephalopathy with cavitations in white matter, as well as neuroregression with illness and episodes of subacute encephalopathy. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in non-patient cells showing impaired mitochondrial function due to gene knockdown, and rescue of the mitochondrial dysfunction in a null yeast model following expression of the wildtype protein (PMIDs: 28844695, 23168492, 25914718). In summary, there is definitive evidence to support the relationship between *LYRM7* 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 April 4, 2022 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Biochemical; 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 LYRM7 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_181705.4. 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 | 2 | 3 | 5 | |||
| missense | 1 | 1 | 25 | 3 | 30 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 1 | 4 | |||
| splice donor/acceptor (+/-2bp) | 1 | 4 | 2 | 7 | ||
| Total | 6 | 9 | 29 | 6 | 0 | 50 |
Highest pathogenic variant AF is 0.0000050400104
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_859056.2 | 5 | MANE Select | |
| Ensembl | ENSP00000368688.4 | 5 | MANE Select | |
| RefSeq | NP_001280664.1 | 4 | Standard | |
| Ensembl | ENSP00000423991.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- mitochondrial respiratory chain complex III assembly
- cellular respiration
Molecular Function
- protein binding
Cellular Component
- mitochondrial matrix
- mitochondrial membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000379380
- Coding exons
- 5
- Length
- 34617
- Individuals with no LoFs
- 125546
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125549
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.737 | 29 | 42.5 | 0.682 | 0.00000180 | 668 |
| Missense (PolyPhen) | 3 | 12.731 | 0.23564 | 225 | ||
| Synonymous | -0.0358 | 15 | 14.8 | 1.01 | 6.36e-7 | 179 |
| Loss of Function | 0.915 | 3 | 5.26 | 0.570 | 2.22e-7 | 78 |
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) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Assembly factor required for Rieske Fe-S protein UQCRFS1 incorporation into the cytochrome b-c1 (CIII) complex. Functions as a chaperone, binding to this subunit within the mitochondrial matrix and stabilizing it prior to its translocation and insertion into the late CIII dimeric intermediate within the mitochondrial inner membrane. {ECO:0000269|PubMed:23168492}.;
- Disease
- DISEASE: Mitochondrial complex III deficiency, nuclear 8 (MC3DN8) [MIM:615838]: A form of mitochondrial complex III deficiency, a disorder of the mitochondrial respiratory chain resulting in a highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. {ECO:0000269|PubMed:24014394}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.613
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 56.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.231
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |