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Intellectual disability

Gene: VARS

Green List (high evidence)
VARS (valyl-tRNA synthetase)
EnsemblGeneIds (GRCh38): ENSG00000204394
EnsemblGeneIds (GRCh37): ENSG00000204394
OMIM: 192150, Gene2Phenotype
VARS is in 2 panels

3 reviews

Louise Daugherty (Genomics England Curator)

Added new-gene-name tag, new approved HGNC gene symbol for VARS is VARS1
Created: 6 Sep 2019, 2:21 p.m. | Last Modified: 6 Sep 2019, 2:21 p.m.
Panel Version: 2.1022
Created: 6 Sep 2019, 2:21 p.m.
Last Modified: 6 Sep 2019, 2:21 p.m.
Panel version: 2.1022

Catherine Snow (Genomics England)

Comment on list classification: Gene status was changed from to Green due to a expert review by Konstantinos Varvagiannis. VARS is associated with phenotype in OMIM and not in Gen2Phen. ID and DD identified in sufficient unrelated cases for VARS to be rated green on the ID panel. VARS has already been reviewed and promoted to Green on the epilepsy panel.
Created: 23 May 2019, 3:55 p.m.
Created: 23 May 2019, 3:55 p.m.

Panel version: Imported from Intellectual disability update May 2019 panel version 0.81

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 26539891 is the first report on individuals with biallelic pathogenic variants in VARS. 3 individuals from 2 consanguineous families are briefly reported. The phenotype was similar in all 3, consisting of severe developmental delay, microcephaly, seizures and cortical atrophy. Subjects from the first family were homozygous for a missense variant in the tRNA synthetase catalytic domain [p.(L885F)]. The patient from the second family was homozygous for a missense SNV affecting the anticodon-binding domain [p.(R1058Q)].

PMID: 29691655 reports on a further patient born to non-consanguineous parents, with 2 in-trans pathogenic variants in VARS. The phenotype consisted of progressive microcephaly (OFC at birth -2SD, at the age of 2 months -4SD), global developmental delay, seizures and progressive cerebral and cerebellar atrophy. An affected brother presented with more severe phenotype (OFC -6SD at birth and -8SD at 2 months of age), seizures, hearing loss but was deceased and unavailable for genetic testing. cDNA studies demonstrated absence of the reference allele for the missense mutation downstream the splice variant (in line with a reduced or absent mRNA allele harboring the splice variant). Similarly, mRNA expression studies demonstrated 50-60% reduction in the transcripts (due to NMD of the allele with the splice SNV). Western blot showed severe reduction in protein levels (more pronounced compared to what would be expected by mRNA expression) presumably secondary to decreased protein stability due to the missense variant. Severe defects in aminoacylation were further confirmatory of a pathogenic role of these variants. The missense variant was affecting the anticodon-binding domain, important for aminoacylation.

PMID: 30275004 reports on 2 siblings with developmental delay, intellectual disability, severe speech impairment and microcephaly, similar to what has been described for the disorder. Clinical findings were somewhat different from previous studies in that microcephaly was acquired, while seizures and cortical atrophy were not part of the phenotype. Both sibs were compound heterozygous for 2 missense variants, though only one of these mutations affected the anticodon binding domain and the other was in the N-terminal region of the protein. Previous metabolic studies and extensive genetic testing (karyotype, CMA, MECP2, FMR1) was normal.

Epilepsy was a feature in 4 of the 6 individuals for whom genetic testing was possible (or 5/7 in total).

VARS belongs to the family of amino acyl-tRNA synthetases (ARSs). Mutations in several cytoplasmic ARSs are associated with severe neurological manifestations including seizures, intellectual disability associated with microcephaly.

VARS is included in gene panels for intellectual disability (but not for epilepsy) offered by different diagnostic labs.

As a result this gene can be considered for inclusion in the ID and epilepsy panel as green (or amber).
Sources: Expert Review, Literature
Created: 17 Oct 2018, 12:17 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
# 617802. NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND CORTICAL ATROPHY; NDMSCA

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 17 Oct 2018, 12:17 p.m.

Panel version: 2.510

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Expert Review
Phenotypes
  • NDMSCA
  • Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, 617802
  • # 617802. NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND CORTICAL ATROPHY
Tags
new-gene-name
OMIM
192150
Clinvar variants
Variants in VARS
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

6 Sep 2019, Gel status: 3

Added Tag

Louise Daugherty (Genomics England Curator)

Tag new-gene-name tag was added to gene: VARS.

25 Jul 2019, Gel status: 3

Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to VARS. Added phenotypes Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, 617802 for gene: VARS Publications for gene VARS were changed from 26539891; 29691655; 30275004 to 26539891; 30275004; 29691655 Rating Changed from No List (delete) to Green List (high evidence)

17 Oct 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: VARS was added gene: VARS was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: VARS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VARS were set to 26539891; 29691655; 30275004 Phenotypes for gene: VARS were set to # 617802. NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND CORTICAL ATROPHY; NDMSCA Penetrance for gene: VARS were set to Complete Review for gene: VARS was set to GREEN gene: VARS was marked as current diagnostic