Infantile liver failure syndrome 1

Summary

Infantile liver failure syndrome 1 (MONDO:0024568) is a disease caused by LARS1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LARS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 24
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile liver failure syndrome 1
Mondo ID	MONDO:0024568
OMIM	615438
Orphanet	370088
DOID	DOID:0080717
UMLS	C3809522
MedGen	815852
GARD	0013114
Is cancer (heuristic)	no

Also known as: ILFS1 · infantile liver failure caused by mutation in LARS · infantile liver failure caused by mutation in Lars · infantile liver failure syndrome 1 · infantile liver failure syndrome type 1 · LARS infantile liver failure · Lars infantile liver failure

Data availability: 24 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › infantile liver failure › infantile liver failure syndrome 1

Related subtypes (3): acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, infantile liver failure syndrome 2, infantile liver failure syndrome 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

24 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 5 conflicting classifications of pathogenicity, 2 pathogenic, 2 benign/likely benign, 2 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048520	NM_020117.11(LARS1):c.2504A>G (p.Tyr835Cys)	LARS1	Pathogenic	criteria provided, single submitter
214577	NM_020117.11(LARS1):c.3313C>T (p.Arg1105Ter)	LARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65476	NM_020117.11(LARS1):c.1118A>G (p.Tyr373Cys)	LARS1	Pathogenic	no assertion criteria provided
2690634	NM_020117.11(LARS1):c.2781del (p.Lys927fs)	LARS1	Likely pathogenic	criteria provided, single submitter
3362591	NM_020117.11(LARS1):c.3325+1del	LARS1	Likely pathogenic	criteria provided, single submitter
1343694	NM_020117.11(LARS1):c.3286A>G (p.Ile1096Val)	LARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343775	NM_020117.11(LARS1):c.2770-2A>G	LARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699493	NM_020117.11(LARS1):c.554C>T (p.Pro185Leu)	LARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388896	NM_020117.11(LARS1):c.1284G>A (p.Pro428=)	LARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
431849	NM_020117.11(LARS1):c.1292T>A (p.Val431Asp)	LARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028641	NM_020117.11(LARS1):c.1439A>G (p.Asp480Gly)	LARS1	Uncertain significance	criteria provided, single submitter
1029737	NM_020117.11(LARS1):c.185G>A (p.Gly62Glu)	LARS1	Uncertain significance	criteria provided, single submitter
1029738	NM_020117.11(LARS1):c.970T>G (p.Phe324Val)	LARS1	Uncertain significance	criteria provided, single submitter
1702970	NM_020117.11(LARS1):c.903del (p.Gln302fs)	LARS1	Uncertain significance	criteria provided, single submitter
2692342	NM_020117.11(LARS1):c.1094C>G (p.Pro365Arg)	LARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3341323	NM_020117.11(LARS1):c.3377G>A (p.Arg1126Gln)	LARS1	Uncertain significance	criteria provided, single submitter
3362703	NM_020117.11(LARS1):c.536A>T (p.His179Leu)	LARS1	Uncertain significance	criteria provided, single submitter
4537430	NM_020117.11(LARS1):c.706C>T (p.Arg236Trp)	LARS1	Uncertain significance	criteria provided, single submitter
4819755	NM_020117.11(LARS1):c.1420G>A (p.Glu474Lys)	LARS1	Uncertain significance	criteria provided, single submitter
4819793	NM_020117.11(LARS1):c.2456A>C (p.Glu819Ala)	LARS1	Uncertain significance	criteria provided, single submitter
561050	NM_020117.11(LARS1):c.242G>T (p.Gly81Val)	LARS1	Uncertain significance	criteria provided, single submitter
138077	NM_020117.11(LARS1):c.245A>G (p.Lys82Arg)	LARS1	Benign	criteria provided, multiple submitters, no conflicts
138089	NM_020117.11(LARS1):c.2212+13T>C	LARS1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
214565	NM_020117.11(LARS1):c.109T>G (p.Leu37Val)	LOC129389388	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
LARS1	Strong	Autosomal recessive	infantile liver failure syndrome 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LARS1	Orphanet:370088	Acute infantile liver failure-multisystemic involvement syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LARS1	HGNC:6512	ENSG00000133706	Q9P2J5	Leucine–tRNA ligase, cytoplasmic	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LARS1	Leucine–tRNA ligase, cytoplasmic	Aminoacyl-tRNA synthetase that catalyzes the specific attachment of leucine to its cognate tRNA (tRNA(Leu)).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LARS1	Enzyme (other)	yes	6.1.1.4	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Leu-tRNA-synth_Ia_arc/euk

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LARS1	292	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LARS1	3,514

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LARS1	Q9P2J5	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cytosolic tRNA aminoacylation	1	439.2×	0.014	LARS1
tRNA Aminoacylation	1	285.5×	0.014	LARS1
Selenoamino acid metabolism	1	196.9×	0.014	LARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.014	LARS1
MITF-M-regulated melanocyte development	1	114.2×	0.018	LARS1
Metabolism of amino acids and derivatives	1	67.6×	0.023	LARS1
Translation	1	62.1×	0.023	LARS1
Developmental Biology	1	14.5×	0.086	LARS1
Metabolism of proteins	1	12.4×	0.086	LARS1
Metabolism	1	11.6×	0.086	LARS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glutaminyl-tRNA aminoacylation	1	8426.0×	5e-04	LARS1
leucyl-tRNA aminoacylation	1	8426.0×	5e-04	LARS1
cellular response to L-leucine	1	1404.3×	0.001	LARS1
cellular response to leucine starvation	1	1404.3×	0.001	LARS1
tRNA aminoacylation for protein translation	1	842.6×	0.002	LARS1
cellular response to amino acid starvation	1	318.0×	0.003	LARS1
cellular response to amino acid stimulus	1	306.4×	0.003	LARS1
positive regulation of TORC1 signaling	1	295.6×	0.003	LARS1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LARS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LARS1	35	Binding:32, ADMET:2, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LARS1	6.1.1.4	leucine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	LARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LARS1	35	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05514470	Not specified	WITHDRAWN	Impact of Mutations in Aminoacyl tRNA Synthetases on Protein Translation and Cellular Stress