AARS2

protein-coding

alanyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class II

Gene summary

The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]

Previous symbols:

AARSL

MANE transcript

NM_020745.4

Inheritance

AR, AD

ClinVar variants

P:84U:295B:163

Top phenotype

Leukoencephalopathy, progressive, with ovarian failure

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr6:44,298,731-44,313,347

External References & Databases

Ensembl (ENSG00000124608)

Transcript & Mutation Effects

hg38 • Region Span ~14.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation defect type 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013570

Submitter: Ambry Genetics

hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented gliaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009096

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *AARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 18, 2022. The *AARS2* gene encodes mitochondrial alanyl-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 *AARS2* gene was first reported in relation to autosomal recessive mitochondrial disease in 2011 (PMID: 21549344). While various names have been given to the constellation of features seen in those with *AARS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *AARS2* 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 11 unique variants, including two nonsense, one frameshift, one in-frame deletion, and seven missense variants. Multi-exon deletions are also reported in the literature (PMID: 30285085). Of note, the c.1774C>T (p.Arg592Trp) variant is a founder variant frequently observed in European populations (PMID: 25705216). Additional recurrent variants include c.149T>G (p.Phe50Cys) and c.595C>T (p.Arg199Cys); and some missense variants have been shown to have similar function to null alleles (PMID: 24808023). There are at least 20 probands from seven publications in 2011-2020 reported with pathogenic variants in this gene (PMIDs: 21549344, 24808023, 31099476, 30285085, 31705293, 25705216). The first individuals described were of Finnish descent and had hypertrophic cardiomyopathy, weakness, and lactic acidosis which was ultimately fatal. Subsequent publications have expanded the phenotype and there now appear to be two main categories: an infantile-onset, rapidly progressive cardiomyopathy with weakness and metabolic abnormalities (PMID: 25705216) or childhood to young adult-onset ovarian failure and leukoencephalopathy (PMID: 24808023). There have also been some patients reported without leukoencephalopathy but with clear cerebellar disease (PMID: 31705293). This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, patient cell studies showing profound respiratory chain deficiencies and mis-assembly, and E. Coli and mouse models (PMIDs: 29228266, 30285085, 24808023, 29980628). 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 April 18, 2022 (SOP Version 8).

leukoencephalopathy, progressive, with ovarian failureMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014387

Submitter: Ambry Genetics

combined oxidative phosphorylation defect type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013570

Submitter: Labcorp Genetics (formerly Invitae)

leukoencephalopathy, progressive, with ovarian failureSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014387

Submitter: Labcorp Genetics (formerly Invitae)

ovarioleukodystrophySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020506

Submitter: Orphanet

combined oxidative phosphorylation defect type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013570

Submitter: PanelApp Australia

leukoencephalopathy, progressive, with ovarian failureSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014387

Submitter: PanelApp Australia

leukoencephalopathy, progressive, with ovarian failureDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014387

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.

combined oxidative phosphorylation defect type 8SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013570

Submitter: Orphanet

Clinical Genomic Database (CGD)

Leukoencephalopathy, progressive, with ovarian failureAR

Manifestation: Biochemical; Cardiovascular; Endocrine; Musculoskeletal; Neurologic; Obstetric

Intervention: Obstetric

Rationale: Females may suffer from premature ovarian failure, and measures to allow reproduction (eg,through egg preservation) may be desired

Refs: 21549344; 24808023; 25058219

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AARS2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 466

Inborn genetic diseasesTotal: 156

Combined oxidative phosphorylation defect type 8Total: 117

not specifiedTotal: 113

AARS2-related disorderTotal: 40

Leukoencephalopathy, progressive, with ovarian failureTotal: 40

Cardiovascular phenotypeTotal: 28

Mitochondrial diseaseTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020745.4. 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			9 clinvar	117 clinvar	2 clinvar	128
missense	8 clinvar	19 clinvar	282 clinvar	41 clinvar	3 clinvar	353
nonsense	8 clinvar	11 clinvar				19
start loss		1 clinvar				1
frameshift	11 clinvar	16 clinvar	1 clinvar			28
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	3 clinvar			13
Total	31	53	295	158	5	542

Highest pathogenic variant AF is 0.00024721128

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020745.4	RefSeq	NP_065796.2	22	MANE Select
ENST00000244571.5	Ensembl	ENSP00000244571.4	22	MANE Select
ENST00000856735.1	Ensembl	ENSP00000526794.1	20	Standard
ENST00000856735.2	Ensembl	ENSP00000526794.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Pyruvate Carboxylase Deficiency
Primary Hyperoxaluria Type I
Lactic Acidemia
Alanine Metabolism

Biological Process

tRNA modification
alanyl-tRNA aminoacylation
mitochondrial respiratory chain complex assembly
mitochondrial alanyl-tRNA aminoacylation

Molecular Function

tRNA binding
alanine-tRNA ligase activity
ATP binding
zinc ion binding
amino acid binding

Cellular Component

mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000244571
Coding exons: 22
Length: 13673
Individuals with no LoFs: 125628
Homozygous LoFs: 0
Heterozygous LoFs: 120
Defined: 125748
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0725	567	572	0.991	0.0000363	6235
Missense (PolyPhen)		192	214.6	0.89468		2413
Synonymous	1.88	198	235	0.844	0.0000134	2157
Loss of Function	2.56	35	55.6	0.630	0.00000345	547

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00043	rare
Latino/Admixed American	0.00052	0.00052	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00055	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00067	0.00067	rare
South Asian	0.00023	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala- AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged tRNA(Ala) via its editing domain. {ECO:0000255|HAMAP-Rule:MF_03133}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 8 (COXPD8) [MIM:614096]: A mitochondrial disease characterized by a lethal infantile hypertrophic cardiomyopathy, generalized muscle dysfunction and some neurologic involvement. The liver is not affected. {ECO:0000269|PubMed:21549344}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukoencephalopathy, progressive, with ovarian failure (LKENP) [MIM:615889]: An autosomal recessive neurodegenerative disorder characterized by childhood- to adulthood-onset of signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. Brain MRI shows leukoencephalopathy with striking involvement of deep white matter, and cerebellar atrophy. All female patients develop premature ovarian failure. {ECO:0000269|PubMed:24808023}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.814
RVIS EVS: 1.14
RVIS percentile EVS: 92.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium