QARS1

Chr 3AR

glutaminyl-tRNA synthetase 1

Also known as: GLNRS, MSCCA, PRO2195, QARS

NCBI Gene: 5859 ENSG00000172053 UniProt: P47897 OMIM: 603727

Glutaminyl-tRNA synthetase catalyzes the attachment of glutamine to its cognate tRNA molecules, playing a critical role in brain development. Biallelic mutations cause autosomal recessive microcephaly with progressive seizures and cerebral and cerebellar atrophy. The gene shows minimal constraint against loss-of-function variants (very low pLI), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. In metazoans, 9 aminoacyl-tRNA synthetases specific for glutamine (gln), glutamic acid (glu), and 7 other amino acids are associated within a multienzyme complex. Although present in eukaryotes, glutaminyl-tRNA synthetase (QARS) is absent from many prokaryotes, mitochondria, and chloroplasts, in which Gln-tRNA(Gln) is formed by transamidation of the misacylated Glu-tRNA(Gln). Glutaminyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.811 OMIM phenotype

Clinical Summary— QARS1

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Gene-Disease Validity (ClinGen)

diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.000

Z-score 2.64

OE 0.59 (0.43–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.22Z-score

OE missense 0.97 (0.90–1.05)

438 obs / 451.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.43–0.81)

0≤0.351.4

Missense OE?0.97 (0.90–1.05)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 28 / 47.6Missense obs/exp: 438 / 451.2Syn Z: -1.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongQARS1-related microcephaly, progressive, seizures, and cerebral and cerebellar atrophyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6259th %ile

GOF

0.5464th %ile

LOF

0.3356th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.