NM_018122.5(DARS2):c.1441G>A (p.Val481Met) AND Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 23, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003152935.1

Allele description [Variation Report for NM_018122.5(DARS2):c.1441G>A (p.Val481Met)]

NM_018122.5(DARS2):c.1441G>A (p.Val481Met)

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.1441G>A (p.Val481Met)

HGVS:

NC_000001.11:g.173853445G>A
NG_016138.1:g.33787G>A
NM_001365212.1:c.1288G>A
NM_018122.5:c.1441G>AMANE SELECT
NP_001352141.1:p.Val430Met
NP_060592.2:p.Val481Met
LRG_1270t1:c.1441G>A
LRG_1270:g.33787G>A
LRG_1270p1:p.Val481Met
NC_000001.10:g.173822583G>A

Protein change:

V430M

Molecular consequence:

NM_001365212.1:c.1288G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_018122.5:c.1441G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (LBSL)
Synonyms:: MITOCHONDRIAL ASPARTYL-tRNA SYNTHETASE DEFICIENCY; Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation; LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION, MILD
Identifiers:: MONDO: MONDO:0012622; MedGen: C1970180; Orphanet: 137898; OMIM: 611105

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003841502	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33977142, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003841502

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 23, 2023)

unknown

clinical testing

PubMed (2)
[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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

Stellingwerff MD, Figuccia S, Bellacchio E, Alvarez K, Castiglioni C, Topaloglu P, Stutterd CA, Erasmus CE, Sanchez-Valle A, Lebon S, Hughes S, Schmitt-Mechelke T, Vasco G, Chow G, Rahikkala E, Dallabona C, Okuma C, Aiello C, Goffrini P, Abbink TEM, Bertini ES, Van der Knaap MS.

Neurol Genet. 2021 Apr;7(2):e559. doi: 10.1212/NXG.0000000000000559.

PubMed [citation]

PMID:: 33977142
PMCID:: PMC8105885

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From 3billion, SCV003841502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 33977142). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DARS2-related disorder (PMID: 33977142). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Mar 26, 2023

ClinVar

Relating variation to medicine