NM_018122.5(DARS2):c.788G>A (p.Arg263Gln) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 25, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002243611.13

Allele description [Variation Report for NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)]

NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)

Gene:

DARS2:aspartyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q25.1

Genomic location:

Preferred name:

NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)

HGVS:

NC_000001.11:g.173838207G>A
NG_016138.1:g.18549G>A
NM_001365212.1:c.788G>A
NM_001365213.2:c.788G>A
NM_018122.5:c.788G>AMANE SELECT
NP_001352141.1:p.Arg263Gln
NP_001352142.1:p.Arg263Gln
NP_060592.2:p.Arg263Gln
LRG_1270t1:c.788G>A
LRG_1270:g.18549G>A
LRG_1270p1:p.Arg263Gln
NC_000001.10:g.173807345G>A
NM_018122.4:c.788G>A
Q6PI48:p.Arg263Gln

Protein change:

R263Q; ARG263GLN

Links:

UniProtKB: Q6PI48#VAR_037020; OMIM: 610956.0004; dbSNP: rs121918207

NCBI 1000 Genomes Browser:

rs121918207

Molecular consequence:

NM_001365212.1:c.788G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001365213.2:c.788G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_018122.5:c.788G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002512899	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 18, 2022)	germline	clinical testing	Citation Link,
SCV003523359	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 25, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17384640, 23216004, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002512899

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Apr 18, 2022)

germline

clinical testing

Citation Link,

SCV003523359

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 25, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation.

Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krägeloh-Mann I, Smeitink JA, Florentz C, Van Coster R, Pronk JC, van der Knaap MS.

Nat Genet. 2007 Apr;39(4):534-9. Epub 2007 Mar 25.

PubMed [citation]

PMID:: 17384640

Pathogenic mutations causing LBSL affect mitochondrial aspartyl-tRNA synthetase in diverse ways.

van Berge L, Kevenaar J, Polder E, Gaudry A, Florentz C, Sissler M, van der Knaap MS, Scheper GC.

Biochem J. 2013 Mar 1;450(2):345-50. doi: 10.1042/BJ20121564.

PubMed [citation]

PMID:: 23216004

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV002512899.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003523359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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