RARS2
protein-codingarginyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class I
Gene summary
This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
- RARSL
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~76.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012683
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *RARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2022. The *RARS2* gene encodes mitochondrial arginyl-tRNA synthetase 2, one of the mitochondrial aminoacyl-tRNA synthetases, which function in mitochondrial translation by catalyzing the attachment of amino acids to their cognate tRNAs. Defects in tRNA charging can result in impaired synthesis of oxidative phosphorylation complex protein subunits. The *RARS2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2007 (PMID: 17847012). While various names have been given to the constellation of features seen in those with *RARS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *RARS2* 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 17 unique variants including nine missense, three frameshift, three splice-site, one consensus splice-site and one 5'UTR variants from seven publications (PMIDs: 31536827, 33209735, 32071833, 17847012, 20635367, 25809939, 22569581). Affected individuals have been reported to have pontocerebellar hypoplasia type 6 (PCH6), seizures, neurodevelopmental regression, microcephaly, and optic atrophy. The mechanism of disease appears to be loss of function either at the transcript or protein level. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, morpholino knockdown of *rars2* in Zebrafish showing hypoplasia and loss of structural definition in the brain phenotype, and patient cells showing reduced RARS2 protein levels (PMIDs: 22569581, 24639874, 21273289). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed since the first proposal of the association. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on May 4, 2022 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: 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 RARS2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020320.5. 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 | 11 | 200 | 211 | |||
| missense | 2 | 38 | 185 | 18 | 1 | 244 |
| nonsense | 18 | 34 | 1 | 53 | ||
| start loss | 4 | 6 | 10 | |||
| frameshift | 26 | 65 | 2 | 93 | ||
| splice donor/acceptor (+/-2bp) | 6 | 59 | 9 | 74 | ||
| Total | 56 | 202 | 208 | 218 | 1 | 685 |
Highest pathogenic variant AF is 0.00057406776
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_064716.2 | 20 | MANE Select | |
| Ensembl | ENSP00000358549.5 | 20 | MANE Select | |
| RefSeq | NP_001305714.1 | 14 | Standard | |
| RefSeq | NP_001337434.1 | 21 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| rars2 | Danio rerio | Structure: midbrain hindbrain boundary Quality: dorso-ventrally flattened abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
- Hyperornithinemia with gyrate atrophy (HOGA)
- Creatine deficiency, guanidinoacetate methyltransferase deficiency
- L-arginine:glycine amidinotransferase deficiency
- Hyperornithinemia-hyperammonemia-homocitrullinuria [HHH-syndrome]
Biological Process
- tRNA aminoacylation for protein translation
- arginyl-tRNA aminoacylation
- mitochondrial translation
Molecular Function
- RNA binding
- arginine-tRNA ligase activity
- ATP binding
Cellular Component
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000369536
- Coding exons
- 20
- Length
- 75626
- Individuals with no LoFs
- 125645
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 103
- Defined
- 125748
- p
- 0.000410
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0650 | 308 | 305 | 1.01 | 0.0000159 | 3780 |
| Missense (PolyPhen) | 101 | 118.72 | 0.85078 | 1392 | ||
| Synonymous | -0.735 | 115 | 105 | 1.09 | 0.00000562 | 1068 |
| Loss of Function | 1.95 | 27 | 40.3 | 0.669 | 0.00000204 | 472 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00074 | 0.00074 | rare |
| Latino/Admixed American | 0.00020 | 0.00020 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00065 | 0.00065 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00050 | 0.00050 | rare |
| South Asian | 0.00036 | 0.00036 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Pontocerebellar hypoplasia 6 (PCH6) [MIM:611523]: A disorder characterized by an abnormally small cerebellum and brainstem, infantile encephalopathy, generalized hypotonia, lethargy and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition. {ECO:0000269|PubMed:17847012}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.123
Intolerance Scores
- LoFtool
- 0.879
- RVIS EVS
- -0.13
- RVIS percentile EVS
- 43.91
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.964
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |