LARS1

protein-coding

leucyl-tRNA synthetase 1, the group of Aminoacyl tRNA synthetases, Class I

Gene summary

This gene encodes a cytosolic leucine-tRNA synthetase, a member of the class I aminoacyl-tRNA synthetase family. The encoded enzyme catalyzes the ATP-dependent ligation of L-leucine to tRNA(Leu). It is found in the cytoplasm as part of a multisynthetase complex and interacts with the arginine tRNA synthetase through its C-terminal domain. A mutation in this gene was found in affected individuals with infantile liver failure syndrome 1. Alternatively spliced transcript variants of this gene have been observed. [provided by RefSeq, Dec 2015]

Previous symbols:

LARS

MANE transcript

NM_020117.11

Inheritance

ClinVar variants

P:33U:216B:95

Top phenotype

Infantile liver failure syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr5:146,110,566-146,182,696

External References & Databases

Ensembl (ENSG00000133706)

Transcript & Mutation Effects

hg38 • Region Span ~72.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

infantile liver failure syndrome 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0024568

Submitter: Orphanet

infantile liver failure syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024568

Submitter: PanelApp Australia

infantile liver failure syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0024568

Submitter: Labcorp Genetics (formerly Invitae)

inherited retinal dystrophyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: LiferaOmics

Genetic evidence – Published No published cases in this context. Published genetic evidence total = 0/12 Genetic evidence – Our cases Family 1- one proband. Case-level (non-LoF start 1.0; homozygous; consanguinity) = 0.1; segregation = 0; case-control = 0; Family 1 total = 0.1. Family 2- one proband. Case-level (non-LoF start 1.0; homozygous; consanguinity) = 0.1; segregation = 0 (affected brother reported but genotype not provided); case-control = 0; Family 2 total = 0.1. Family 3- one proband. Case-level (non-LoF start 1.0; homozygous; consanguinity ) = 0.1; segregation = 0 (affected relatives reported but genotypes not provided); case-control = 0; Family 3 total = 0.1. Our cases total = 0.1 + 0.1 + 0.1 = 0.3/12 Total genetic evidence (published + our cases) 0 + 0.3 = 0.3/12 Experimental evidence – Published No retinal-disease–specific experimental evidence was identified/available to score at this stage. Experimental evidence total = 0/6 Overall score Overall score = 0.3 + 0 = 0.3/18

Clinical Genomic Database (CGD)

Infantile liver failure syndrome 1AR

Manifestation: Gastrointestinal; Hematologic; Neurologic; Renal

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: 22607940

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LARS1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 322

not specifiedTotal: 210

Infantile liver failure syndrome 1Total: 23

LARS1-related disorderTotal: 13

Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteinsTotal: 9

Generalized-onset seizureTotal: 1

LARS-related disordersTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020117.11. 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			5 clinvar	68 clinvar	5 clinvar	78
missense	2 clinvar	9 clinvar	204 clinvar	19 clinvar	3 clinvar	237
nonsense	6 clinvar	3 clinvar	1 clinvar			10
start loss						0
frameshift	6 clinvar	3 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)		4 clinvar	4 clinvar			8
Total	14	19	216	87	8	344

Highest pathogenic variant AF is 0.0006803151

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020117.11	RefSeq	NP_064502.9	32	MANE Select
ENST00000394434.7	Ensembl	ENSP00000377954.2	32	MANE Select
NM_001317964.2	RefSeq	NP_001304893.1	31	Standard
NM_001317965.2	RefSeq	NP_001304894.1	30	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Aminoacyl-tRNA biosynthesis - Homo sapiens (human)
tRNA Aminoacylation
Translation
Metabolism of proteins
Metabolism of amino acids and derivatives

Biological Process

tRNA aminoacylation for protein translation
glutaminyl-tRNA aminoacylation
leucyl-tRNA aminoacylation
protein targeting to lysosome
regulation of cell size

Molecular Function

aminoacyl-tRNA editing activity
glutamine-tRNA ligase activity
leucine-tRNA ligase activity
GTPase activator activity
protein binding

Cellular Component

cytoplasm
lysosome
endoplasmic reticulum
cytosol
endomembrane system

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394434
Coding exons: 32
Length: 69623
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 77
Defined: 125748
p: 0.000306

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	514	618	0.832	0.0000311	7763
Missense (PolyPhen)		91	151.22	0.60176		1830
Synonymous	0.531	200	210	0.953	0.0000106	2100
Loss of Function	4.83	27	70.8	0.381	0.00000343	895

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00061	0.00061	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00044	0.00044	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00029	0.00029	rare
South Asian	0.00017	0.00016	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the specific attachment of an amino acid to its cognate tRNA in a two step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA. Exhibits a post-transfer editing activity to hydrolyze mischarged tRNAs. {ECO:0000269|PubMed:19426743}.;
Disease: DISEASE: Infantile liver failure syndrome 1 (ILFS1) [MIM:615438]: A life-threatening disorder of hepatic function that manifests with acute liver failure in the first few months of life. Clinical features include anemia, renal tubulopathy, developmental delay, seizures, failure to thrive, and liver steatosis and fibrosis. {ECO:0000269|PubMed:22607940}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.846
RVIS EVS: -0.44
RVIS percentile EVS: 24.68

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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