VCV002202881.5 - ClinVar

NM_018122.5(DARS2):c.796C>T (p.Arg266Ter)

Germline

Classification

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.

(4)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018122.5(DARS2):c.796C>T (p.Arg266Ter)

Variation ID: 2202881 Accession: VCV002202881.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q25.1 1: 173838215 (GRCh38) [ NCBI UCSC ] 1: 173807353 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Feb 8, 2023	May 1, 2024	Oct 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018122.5:c.796C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060592.2:p.Arg266Ter	nonsense
NM_001365212.1:c.796C>T	NP_001352141.1:p.Arg266Ter	nonsense
NM_001365213.2:c.796C>T	NP_001352142.1:p.Arg266Ter	nonsense
NM_018122.4:c.796C>T
NC_000001.11:g.173838215C>T
NC_000001.10:g.173807353C>T
NG_016138.1:g.18557C>T
LRG_1270:g.18557C>T
LRG_1270t1:c.796C>T	LRG_1270p1:p.Arg266Ter

... more HGVS ... less HGVS

Protein change

R266*

Other names

Canonical SPDI

NC_000001.11:173838214:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help 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.
DARS2		-	-	GRCh38 GRCh37	406	454

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 30, 2023	RCV002634321.4
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 19, 2022	RCV002648220.2
Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 11, 2023	RCV003341525.1

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 Help 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 Help 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 Help 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.
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004048890.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023
Likely pathogenic (Oct 30, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004169208.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24566671) (less)
Pathogenic (Jul 18, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003523919.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24566671‚ 17384640 Comment: For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with leukoencephalopathy (PMID: 24566671). This … (more) For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with leukoencephalopathy (PMID: 24566671). This variant is present in population databases (rs149035108, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg266*) in the DARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DARS2 are known to be pathogenic (PMID: 17384640, 24566671). (less)
Pathogenic (Jan 19, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003591070.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 24566671 Comment: The c.796C>T (p.R266) alteration, located in exon 9 (coding exon 9) of the DARS2 gene, consists of a C to T substitution at nucleotide position … (more) The c.796C>T (p.R266) alteration, located in exon 9 (coding exon 9) of the DARS2 gene, consists of a C to T substitution at nucleotide position 796. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 266. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (6/251392) total alleles studied. The highest observed frequency was 0.02% (3/16254) of African alleles. This alteration has been reported with another mutation, p.R76Sfs*5, in DARS2 in a 17 year old male patient with mild developmental delay and normal cognitive ability (van Berge, 2014). Based on the available evidence, this alteration is classified as pathogenic. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with leukoencephalopathy (PMID: 24566671). This variant is present in population databases (rs149035108, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg266*) in the DARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DARS2 are known to be pathogenic (PMID: 17384640, 24566671).

Comment:

The c.796C>T (p.R266*) alteration, located in exon 9 (coding exon 9) of the DARS2 gene, consists of a C to T substitution at nucleotide position 796. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 266. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (6/251392) total alleles studied. The highest observed frequency was 0.02% (3/16254) of African alleles. This alteration has been reported with another mutation, p.R76Sfs*5, in DARS2 in a 17 year old male patient with mild developmental delay and normal cognitive ability (van Berge, 2014). Based on the available evidence, this alteration is classified as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.	van Berge L	Brain : a journal of neurology	2014	PMID: 24566671
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 this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_018122.5(DARS2):c.796C>T (p.Arg266Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...