MARS2

protein-coding

methionyl-tRNA synthetase 2, mitochondrial, the group of Aminoacyl tRNA synthetases, Class I

Gene summary

This gene produces a mitochondrial methionyl-tRNA synthetase protein that is encoded by the nuclear genome and imported to the mitochondrion. This protein likely functions as a monomer and is predicted to localize to the mitochondrial matrix. Mutations in this gene are associated with the autosomal recessive neurodegenerative disease spastic ataxia-3 (SPAX3). [provided by RefSeq, Apr 2014]

MANE transcript

NM_138395.4

Inheritance

ClinVar variants

P:9U:220B:90

Top phenotype

Combined oxidative phosphorylation deficiency 25; Spastic ataxia 3, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr2:197,705,369-197,708,395

External References & Databases

Ensembl (ENSG00000247626)

Transcript & Mutation Effects

hg38 • Region Span ~3.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic ataxia 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012664

Submitter: Genomics England PanelApp

spastic ataxia 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012664

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation defect type 25LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014636

Submitter: Ambry Genetics

combined oxidative phosphorylation defect type 25LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014636

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MARS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2022. The *MARS2* gene encodes mitochondrial methionyl-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 *MARS2* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22448145). This paper described the molecular etiologies in families originally reported in 2006 (PMID: 16672289). While various names have been given to the constellation of features seen in those with *MARS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MARS2* 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 five unique variants (three complex rearrangements, each determined to be a founder variant within the French-Canadian population, one missense variant, and one stop-gained variant) identified in five individuals from two publications (PMIDs: 22448145, 25754315). Affected individuals were reported to have leukoencephalopathy, cerebellar vermis atrophy, dystonia, ataxia, spasticity, and dysarthria. The phenotype of affected individuals with the French-Canadian founder variant or other complex rearrangements has been termed **a**utosomal **r**ecessive **s**pastic **a**taxia with **l**eukoencephalopathy (ARSAL; PMID: 22448145). 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 HEK293 cells showing disrupted mitochondrial protein translation, evidence of mitochondrial dysfunction in patient cells, and early lethality and mitochondrial dysfunction in two independent Drosophila models, each homozygous for a missense change (PMID: 22448145). 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).

mitochondrial diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 25; Spastic ataxia 3, autosomal recessiveAR

Manifestation: Biochemical; Craniofacial; 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

Refs: 22448145; 25754315

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MARS2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 240

not specifiedTotal: 117

MARS2-related disorderTotal: 16

Spastic ataxia 3Total: 11

Combined oxidative phosphorylation defect type 25Total: 9

MARS2-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138395.4. 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			11 clinvar	75 clinvar	4 clinvar	90
missense		2 clinvar	195 clinvar	10 clinvar	1 clinvar	208
nonsense		3 clinvar	7 clinvar			10
start loss		1 clinvar	2 clinvar			3
frameshift	2 clinvar	1 clinvar	5 clinvar			8
splice donor/acceptor (+/-2bp)						0
Total	2	7	220	85	5	319

Highest pathogenic variant AF is 0.000020533853

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138395.4	RefSeq	NP_612404.1	1	MANE Select
ENST00000282276.8	Ensembl	ENSP00000282276.6	1	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Selenocompound metabolism - Homo sapiens (human)
Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
miR-targeted genes in lymphocytes - TarBase
Amino Acid metabolism
tRNA Aminoacylation

Biological Process

tRNA aminoacylation for protein translation
methionyl-tRNA aminoacylation

Molecular Function

methionine-tRNA ligase activity
ATP binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000282276
Coding exons: 1
Length: 3027
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	0.299	316	331	0.954	0.0000163	3808
Missense (PolyPhen)		107	108.89	0.98265		1274
Synonymous	-1.02	160	144	1.11	0.00000703	1297
Loss of Function	1.99	10	19.5	0.514	9.54e-7	196

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: dbNSFP

Disease: DISEASE: Spastic ataxia 3, autosomal recessive (SPAX3) [MIM:611390]: A neurologic disorder characterized by cerebellar ataxia, ataxic gait, spasticity, and hyperreflexia. Other variable features include dysarthria, dysmetria, mild cognitive impairment, urinary urgency and dystonic positioning. {ECO:0000269|PubMed:22448145}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Combined oxidative phosphorylation deficiency 25 (COXPD25) [MIM:616430]: A mitochondrial disorder resulting in developmental delay, growth failure, and sensorineural hearing loss. {ECO:0000269|PubMed:25754315}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.193

Intolerance Scores

LoFtool: 0.746
RVIS EVS: -0.84
RVIS percentile EVS: 11.18

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.822

Gene Damage Prediction

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