LARS2

Chr 3AR

leucyl-tRNA synthetase 2, mitochondrial

Also known as: HLASA, LEURS, PRLTS4, mtLeuRS

NCBI Gene: 23395 ENSG00000011376 UniProt: Q15031 OMIM: 604544

The protein is mitochondrial leucyl-tRNA synthetase, which catalyzes the attachment of leucine to its cognate tRNA for mitochondrial protein synthesis. Biallelic mutations cause autosomal recessive disorders including hydrops with lactic acidosis and sideroblastic anemia, and Perrault syndrome 4 (ovarian dysgenesis with sensorineural hearing loss). Pathogenicity results from impaired mitochondrial protein synthesis leading to mitochondrial dysfunction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hydrops, lactic acidosis, and sideroblastic anemiaMIM #617021

Perrault syndrome 4MIM #615300

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Perrault syndrome · AR · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.86

LOEUF

—

Mechanism

📖

GeneReview available — LARS2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.40

OE 0.64 (0.49–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.33Z-score

OE missense 0.83 (0.77–0.90)

427 obs / 511.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.64 (0.49–0.86)

0≤0.351.4

Missense OE?0.83 (0.77–0.90)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 34 / 52.8Missense obs/exp: 427 / 511.7Syn Z: 0.48

Background carrier burden — how many people carry a rare variant somewhere in LARS2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 69

1,047 rare PASS variants

Rare truncating (LoF)

1 in 1,000

171 rare PASS variants

Rare synonymous (reference)

1 in 84

415 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LARS2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 97	1 in 1,200
South Asian	~43k	1 in 56	1 in 810
Remaining (unassigned)	~30k	1 in 49	1 in 1,900
European (Finnish)	~27k	1 in 250	1 in 3,800
Admixed American	~22k	1 in 48	1 in 1,400
African / African American	~21k	1 in 53	1 in 980
East Asian	~20k	1 in 72	1 in 320
Ashkenazi Jewish	~13k	1 in 200	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 65	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 18 of 20 coding exons well covered in gnomAD exomes; exons 7, 11 marginal. Genomes: all 20.? see exons ↓