VARS1

protein-coding

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

Gene summary

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. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]

Previous symbols:

VARS2
VARS

MANE transcript

NM_006295.3

Inheritance

ClinVar variants

P:41U:250B:52

Top phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr6:31,777,518-31,795,752

External References & Databases

Ensembl (ENSG00000204394)

Transcript & Mutation Effects

hg38 • Region Span ~18.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with microcephaly, seizures, and cortical atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060621

Submitter: ClinGen

The VARS1 gene is located on chromosome 6 at 6p21.33 and encodes the valyl-tRNA synthetase 1 protein. VARS1 plays a key role in protein translation as the cytoplasmic aminoacyl-tRNA synthetase responsible for catalyzing the attachment of valine to its cognate transfer RNA (tRNA) molecule. VARS1 was first reported in relation to autosomal recessive neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy in 2015 (Karaca et al. 2015 26539891). The disorder is characterized by a severe global developmental delay, acquired microcephaly (typically present by 6 months of age) and an onset of seizures during early infancy (Friedman et al. 2019; Siekierska et al. 2019). Seizure types vary between affected cases and may include myoclonia, focal clonic seizures and or generalized seizures. Brain abnormalities detected by MRI are also variable, cortical atrophy being the most common feature. Partial agenesis or hypoplasia of the corpus callosum are frequently seen, as well as cerebellar atrophy. Seventeen variants (including 14 missense, 1 frameshift, 1 stop gained and 1 canonical splice site variant), that have been reported in 12 probands in five publications (PMIDs: 26539891, 29137650, 29691655, 30755616, 30755602) are included in this curation. The mechanism of disease is biallelic loss of function. This gene-disease relationship is also supported by expression studies and other aminoacyl-tRNA synthetases have been associated with gene disease relationships characterized neurodevelopmental phenotypes (PMID: 25035493). A zebrafish vars1 knockout model, generated using CRISPR/Cas9 technology, recapitulates the brain malformation, developmental delay and seizure phenotypes observed in the clinical phenotype. In summary, there is definitive evidence to support the relationship between VARS1 and autosomal recessive neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date December 6th, 2023 (SOP Version 10).

combined oxidative phosphorylation defect type 20SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014397

Submitter: Orphanet

neurodevelopmental disorder with microcephaly, seizures, and cortical atrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0060621

Submitter: Illumina

neurodevelopmental disorder with microcephaly, seizures, and cortical atrophySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060621

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophyAR

Manifestation: Craniofacial; Neurologic

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: 26539891; 29691655

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VARS1 variants in ClinVar

14 Conditions Cataloged

Inborn genetic diseasesTotal: 198

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophyTotal: 79

not providedTotal: 75

VARS1-related disorderTotal: 18

not specifiedTotal: 9

Elevated circulating hepatic transaminase concentrationTotal: 2

Generalized hypotoniaTotal: 2

Premature birthTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006295.3. 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			6 clinvar	27 clinvar	5 clinvar	38
missense	4 clinvar	16 clinvar	234 clinvar	15 clinvar	5 clinvar	274
nonsense	5 clinvar	6 clinvar	3 clinvar			14
start loss						0
frameshift	3 clinvar	2 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)	2 clinvar	3 clinvar	5 clinvar			10
Total	14	27	250	42	10	343

Highest pathogenic variant AF is 0.00007502145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006295.3	RefSeq	NP_006286.1	29	MANE Select
ENST00000375663.8	Ensembl	ENSP00000364815.3	29	MANE Select
ENST00000428445.1	Ensembl	ENSP00000415679.1	10	Standard
ENST00000440048.1	Ensembl	ENSP00000413925.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
vars	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

vars

Danio rerio

Structure: head

Quality: decreased size

abnormal

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
valyl-tRNA aminoacylation
aminoacyl-tRNA metabolism involved in translational fidelity

Molecular Function

aminoacyl-tRNA editing activity
valine-tRNA ligase activity
protein binding
ATP binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375663
Coding exons: 29
Length: 18436
Individuals with no LoFs: 125634
Homozygous LoFs: 0
Heterozygous LoFs: 114
Defined: 125748
p: 0.000453

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.68	577	789	0.731	0.0000509	8069
Missense (PolyPhen)		193	327.57	0.58919		3481
Synonymous	1.99	274	319	0.859	0.0000197	2679
Loss of Function	4.98	27	72.9	0.370	0.00000387	739

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.0023	0.0023	notable
European (Non-Finnish)	0.00039	0.00038	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (NDMSCA) [MIM:617802]: An autosomal recessive neurodevelopmental disorder characterized by severe developmental delay, intellectual disability, severe microcephaly, and cortical atrophy. {ECO:0000269|PubMed:26539891}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0913

Intolerance Scores

LoFtool: 0.626
RVIS EVS: -0.33
RVIS percentile EVS: 30.9

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.999

Gene Damage Prediction

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