ClinVar Genomic variation as it relates to human health
NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)
Variation ID: 1060 Accession: VCV000001060.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q25.1 1: 173838207 (GRCh38) [ NCBI UCSC ] 1: 173807345 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 28, 2017 Mar 4, 2023 Jun 25, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018122.5:c.788G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060592.2:p.Arg263Gln missense NM_001365212.1:c.788G>A NP_001352141.1:p.Arg263Gln missense NM_001365213.2:c.788G>A NP_001352142.1:p.Arg263Gln missense NC_000001.11:g.173838207G>A NC_000001.10:g.173807345G>A NG_016138.1:g.18549G>A LRG_1270:g.18549G>A LRG_1270t1:c.788G>A LRG_1270p1:p.Arg263Gln Q6PI48:p.Arg263Gln - Protein change
- R263Q
- Other names
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- Canonical SPDI
- NC_000001.11:173838206:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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DARS2 | - | - |
GRCh38 GRCh37 |
406 | 454 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Feb 17, 2016 | RCV000001115.16 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 25, 2022 | RCV002243611.13 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 17, 2016)
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criteria provided, single submitter
Method: clinical testing
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Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000594312.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Uncertain significance
(Jun 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003523359.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 263 of the DARS2 protein (p.Arg263Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 263 of the DARS2 protein (p.Arg263Gln). This variant is present in population databases (rs121918207, gnomAD 0.005%). This missense change has been observed in individual(s) with Leukoencephalopathy (PMID: 17384640). ClinVar contains an entry for this variant (Variation ID: 1060). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DARS2 protein function. Experimental studies have shown that this missense change affects DARS2 function (PMID: 17384640, 23216004). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Apr 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002512899.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
Identified in the published literature in an individual with LBSL, however a second variant was not identified (Scheper et al., 2007); Functional analysis of recombinant … (more)
Identified in the published literature in an individual with LBSL, however a second variant was not identified (Scheper et al., 2007); Functional analysis of recombinant mutant protein showed significantly impaired enzymatic activity compared to wildtype protein (Scheper et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25476837, 33574740, 23216004, 26620921, 30006346, 34503567, 29305884, 17384640, Rathore2017[Abstract], 34631948) (less)
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Pathogenic
(Apr 01, 2007)
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no assertion criteria provided
Method: literature only
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LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021265.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2018 |
Comment on evidence:
For discussion of the arg263-to-gln (R263Q) mutation in the DARS2 gene that was found in compound heterozygous state in sibs with leukoencephalopathy with brainstem and … (more)
For discussion of the arg263-to-gln (R263Q) mutation in the DARS2 gene that was found in compound heterozygous state in sibs with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; 611105) by Scheper et al. (2007), see 610956.0001. The R263Q substitution results from a 788G-A transition in exon 9. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Affected status: yes
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV000840287.1
First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Failure to thrive (present) , Abnormality of eye movement (present) , Seizures (present) , Generalized hypotonia (present) , Encephalopathy (present) , EEG abnormality (present) , … (more)
Failure to thrive (present) , Abnormality of eye movement (present) , Seizures (present) , Generalized hypotonia (present) , Encephalopathy (present) , EEG abnormality (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Joint hypermobility (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) , Abnormality of the upper respiratory tract (present) , Abnormal pattern of respiration (present) , Restrictive ventilatory defect (present) , Respiratory insufficiency (present) , Abnormality of the diaphragm (present) , Decreased pulmonary function (present) , Asthma (present) , Recurrent infections (present) , Abnormal inflammatory response (present) (less)
Indication for testing: Diagnostic, Leukodystrophy
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: Genetic Services Laboratory,University of Chicago
Date variant was reported to submitter: 2016-02-24
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways. | van Berge L | The Biochemical journal | 2013 | PMID: 23216004 |
Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. | Scheper GC | Nature genetics | 2007 | PMID: 17384640 |
Text-mined citations for rs121918207 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.