LARS2

protein-coding

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

Gene summary

This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]

MANE transcript

NM_015340.4

Inheritance

ClinVar variants

P:74U:236B:160

Top phenotype

Perrault syndrome 4

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr3:45,388,561-45,554,726

External References & Databases

Ensembl (ENSG00000011376)

Transcript & Mutation Effects

hg38 • Region Span ~166.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Perrault syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017312

Submitter: ClinGen

The *LARS2* gene was first associated with autosomal recessive Perrault syndrome in 2013 (Pierce et al., PMID: 23541342). At least 27 unique variants (missense, frameshift) have been reported in 18 probands in 12 publications (PMIDs: 23541342, 26970254, 27650058, 26657938, 29205794, 30737337, 31274036, 32442335, 32399598, 32767731, 32842620, 36450801). Variants in this gene segregated with disease in 7 additional members in one family (PMID: 32842620). An additional internal case at the Laboratory for Molecular Medicine involves two young sisters with profound sensorineural hearing loss, who are compound heterozygous for a missense variant and exon 22 deletion (NM_015340.3(LARS2):c.(?_2533)-70_*(70_?)del, SCV000731480.1). This gene-disease relationship is supported by relevant expression studies, biochemical function studies, a mouse model and a rescue (PMIDs: 23541342, 26537577, 28263850). In summary *LARS2* is definitively associated with autosomal recessive Perrault syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally classified as Strong by the ClinGen Hearing Loss Working Group on 6/26/2018 as per SOP v5. It was reevaluated on 6/1/2023 as per SOP v9. As a result of this reevaluation, the classification increased from Strong to Definitive due to additional case level evidence from new literature (PMIDs: 30737337, 31274036, 32442335, 32399598, 32767731, 32842620, 36450801).

Perrault syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014126

Submitter: Labcorp Genetics (formerly Invitae)

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014869

Submitter: Ambry Genetics

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014869

Submitter: Labcorp Genetics (formerly Invitae)

Perrault syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014126

Submitter: G2P

hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014869

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Perrault syndrome 4AR

Manifestation: Audiologic/Otolaryngologic; Endocrine; Genitourinary; Hematologic; Obstetric; Pulmonary

Intervention: Audiologic/Otolaryngologic; Biochemical; Endocrine; Gastrointestinal; Hematologic; Neurologic; Obstetric

Rationale: Genetic knowledge may allow fertility preservation such as by storing eggs in woman with premature ovarian failure

Refs: 23541342; 26537577; 32442335

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LARS2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 479

Inborn genetic diseasesTotal: 96

not specifiedTotal: 86

Perrault syndrome 4Total: 54

LARS2-related disorderTotal: 51

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndromeTotal: 27

Perrault syndromeTotal: 8

LARS2-Related DisordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015340.4. 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			7 clinvar	131 clinvar	6 clinvar	144
missense	4 clinvar	22 clinvar	219 clinvar	20 clinvar	3 clinvar	268
nonsense	7 clinvar	11 clinvar	1 clinvar			19
start loss						0
frameshift	14 clinvar	4 clinvar	1 clinvar			19
splice donor/acceptor (+/-2bp)	1 clinvar	11 clinvar	8 clinvar			20
Total	26	48	236	151	9	470

Highest pathogenic variant AF is 0.0003481851

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015340.4	RefSeq	NP_056155.1	20	MANE Select
ENST00000645846.2	Ensembl	ENSP00000495093.1	20	MANE Select
NM_001368263.1	RefSeq	NP_001355192.1	20	Standard
ENST00000265537.8	Ensembl	ENSP00000265537.4	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
Amino Acid metabolism
tRNA Aminoacylation
Translation
Metabolism of proteins

Biological Process

tRNA aminoacylation for protein translation
leucyl-tRNA aminoacylation
mitochondrial translation
aminoacyl-tRNA metabolism involved in translational fidelity

Molecular Function

aminoacyl-tRNA editing activity
leucine-tRNA ligase activity
ATP binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000415258
Coding exons: 20
Length: 160916
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	1.33	427	512	0.834	0.0000275	5914
Missense (PolyPhen)		135	209.55	0.64424		2460
Synonymous	0.485	185	194	0.956	0.0000110	1729
Loss of Function	2.40	34	52.8	0.644	0.00000255	587

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00028	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0010	0.0010	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00041	0.00040	rare
South Asian	0.00063	0.00062	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Hydrops, lactic acidosis, and sideroblastic anemia (HLASA) [MIM:617021]: A lethal, multisystem metabolic disorder characterized by severe lactic acidosis, hydrops, and sideroblastic anemia. Additional features include impaired cardiac function, disordered coagulation, pulmonary hypertension, and progressive renal disease. {ECO:0000269|PubMed:26537577}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.233

Intolerance Scores

LoFtool: 0.567
RVIS EVS: -0.75
RVIS percentile EVS: 13.74

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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