NARS2

protein-coding

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

Gene summary

This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of asparagine to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24). [provided by RefSeq, Mar 2015]

Previous symbols:

DFNB94

MANE transcript

NM_024678.6

Inheritance

AR, AD

ClinVar variants

P:40U:163B:76

Top phenotype

Deafness, autosomal recessive 94

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr11:78,435,620-78,575,194

External References & Databases

Ensembl (ENSG00000137513)

Transcript & Mutation Effects

hg38 • Region Span ~139.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NARS2* and *NARS2*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2024. The *NARS2* gene encodes mitochondrial asparaginyl-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 *NARS2* gene was first reported in relation to autosomal recessive *NARS2*-related primary mitochondrial disease in 2015 (PMID: 25629079). *NARS2* has been associated with two disease entities to date; combined oxidative phosphorylation deficiency 24 [OMIM# 616239] and deafness, autosomal recessive 94 [OMIM# 618434]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NARS2*-related primary mitochondrial disease. Of note, *NARS2* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on December 9, 2019 (SOP v7), with a final classification of Limited. This current curation for the association with *NARS2*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 21 unique variants (18 missense, one intronic, one frameshift, one nonsense) identified in 12 unrelated cases from 10 publications (PMIDs: 25629079, 25385316, 25807530, 28077841, 30327238, 32020600, 34374940, 35558980, 33596490, 35703918). Disease onset is typically early in life. Some affected individuals have clinical features consistent with LSS and/or Alpers syndrome, others have an infantile onset of severe epilepsy, and there have been reports of isolated hearing loss. Additional clinical features include myopathy, developmental delay and regression, myoclonic movements, spasticity, ataxia, dysarthria, muscle weakness, seizures include epilepsia partialias continua (EPC), microcephaly, short stature, diabetes, failure to thrive, optic atrophy, ptosis, and sensorineural hearing loss. Elevated lactate and creatine kinase levels have been reported. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in patient muscle tissue (PMIDs: 25807530, 34415467), an embryonic lethal knockout mouse model (PMID: 36305825), and a yeast model (PMID: 39230874). In summary, there is definitive evidence to support the relationship between *NARS2* and autosomal recessive *NARS*2-related 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 December 16, 2024 (SOP Version 10).

combined oxidative phosphorylation defect type 24STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014547

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation defect type 24MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014547

Submitter: Ambry Genetics

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NARS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The NARS2 gene encodes mitochondrial asparaginyl-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 NARS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2015 (PMID: 25807530). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique variants identified in one case from one publication (PMID: 25807530). No segregation data were available. Loss of function is implicated as the mechanism of disease. Of note, this gene has also been implicated in Alpers syndrome and other mitochondrial diseases which will be assessed separately. This gene-disease association is also supported by known biochemical function and rescue studies in patient cells (PMIDs: 29980628, 25807530). 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel December 9, 2019 (SOP Version 7).

hearing loss, autosomal recessive 94LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032749

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

combined oxidative phosphorylation defect type 24STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014547

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 24SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014547

Submitter: Orphanet

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

NARS2 was first reported in relation to autosomal recessive nonsyndromic sensorineural hearing loss (ARNSHL) in 2015 (Simon 2015 PMID:25807530). Of note, this gene has also been associated with Leigh syndrome (Simon 2015), Alpers syndrome (Sofou 2015), and mitochondrial disorder (Vanlander 2015, Wang 2016) and Perrault syndrome in the family described in Simon et al. 2015 could not be ruled out. The split curation for autosomal recessive Leigh syndrome has been curated separately. Two missense variants that have been reported in one proband in one publication is included in this curation. Variants in this gene segregated with disease in 5 additional family members (PMID: 25807530). The mechanism of pathogenicity is unknown. This gene-disease association is also supported by expression studies in human and mouse cochlea. (PMID: 25807530). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 12/19/2017. It was reevaluated on 11/17/2021using SOP v8. As a result of this reevaluation, the classification did not change as no new information was published.

combined oxidative phosphorylation defect type 24DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014547

Submitter: G2P

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: Illumina

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 94AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Musculoskeletal; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 25385316; 25629079; 25807530

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NARS2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 297

Inborn genetic diseasesTotal: 80

Combined oxidative phosphorylation defect type 24Total: 48

NARS2-related disorderTotal: 36

not specifiedTotal: 30

Hearing loss, autosomal recessive 94Total: 11

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1Total: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024678.6. 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 clinvar	1 clinvar	58 clinvar	2 clinvar	62
missense	4 clinvar	10 clinvar	149 clinvar	14 clinvar	2 clinvar	179
nonsense	4 clinvar	5 clinvar	4 clinvar			13
start loss			1 clinvar			1
frameshift	7 clinvar	3 clinvar	1 clinvar			11
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar	7 clinvar			13
Total	18	22	163	72	4	279

Highest pathogenic variant AF is 0.00008058747

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024678.6	RefSeq	NP_078954.4	14	MANE Select
ENST00000281038.10	Ensembl	ENSP00000281038.5	14	MANE Select
NM_001243251.2	RefSeq	NP_001230180.1	9	Standard
NM_001425299.1	RefSeq	NP_001412228.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Ectoderm Differentiation
tRNA Aminoacylation
Translation
Metabolism of proteins

Biological Process

asparaginyl-tRNA aminoacylation

Molecular Function

nucleic acid binding
asparagine-tRNA ligase activity
ATP binding

Cellular Component

nucleoplasm
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281038
Coding exons: 14
Length: 138913
Individuals with no LoFs: 125708
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125747
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.759	292	258	1.13	0.0000131	3108
Missense (PolyPhen)		86	95.418	0.9013		1127
Synonymous	-1.04	100	87.6	1.14	0.00000397	915
Loss of Function	2.12	16	28.2	0.568	0.00000152	331

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000067	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Combined oxidative phosphorylation deficiency 24 (COXPD24) [MIM:616239]: An autosomal recessive mitochondrial disorder with wide phenotypic variability. Some patients have a milder form affecting only skeletal muscle, whereas others may have a more severe disorder, reminiscent of Alpers syndrome. Alpers syndrome is a progressive neurodegenerative disorder that presents in infancy or early childhood and is characterized by diffuse degeneration of cerebral gray matter. {ECO:0000269|PubMed:25385316, ECO:0000269|PubMed:25629079}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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:25807530}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 0.527
RVIS EVS: -0.29
RVIS percentile EVS: 33.42

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.759

Gene Damage Prediction

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