NM_001349.4(DARS1):c.1379G>A (p.Arg460His) AND Hypomyelination with brain stem and spinal cord involvement and leg spasticity

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 2, 2013
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000043686.5

Allele description [Variation Report for NM_001349.4(DARS1):c.1379G>A (p.Arg460His)]

NM_001349.4(DARS1):c.1379G>A (p.Arg460His)

Gene:

DARS1:aspartyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q21.3

Genomic location:

Preferred name:

NM_001349.4(DARS1):c.1379G>A (p.Arg460His)

HGVS:

NC_000002.12:g.135911174C>T
NG_034149.1:g.79511G>A
NM_001293312.1:c.1079G>A
NM_001349.4:c.1379G>AMANE SELECT
NP_001280241.1:p.Arg360His
NP_001340.2:p.Arg460His
NC_000002.11:g.136668744C>T
P14868:p.Arg460His

Protein change:

R360H; ARG460HIS

Links:

UniProtKB: P14868#VAR_070041; OMIM: 603084.0005; dbSNP: rs587776985

NCBI 1000 Genomes Browser:

rs587776985

Molecular consequence:

NM_001293312.1:c.1079G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349.4:c.1379G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypomyelination with brain stem and spinal cord involvement and leg spasticity
Synonyms:: ASPARTYL-tRNA SYNTHETASE DEFICIENCY; Hypomyelination with brainstem and spinal cord involvement and leg spasticity
Identifiers:: MONDO: MONDO:0014115; MedGen: C4755254; Orphanet: 363412; OMIM: 615281

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000071697	OMIM	no assertion criteria provided	Pathogenic (May 2, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000071697

OMIM

no assertion criteria provided

Pathogenic
(May 2, 2013)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.

Taft RJ, Vanderver A, Leventer RJ, Damiani SA, Simons C, Grimmond SM, Miller D, Schmidt J, Lockhart PJ, Pope K, Ru K, Crawford J, Rosser T, de Coo IF, Juneja M, Verma IC, Prabhakar P, Blaser S, Raiman J, Pouwels PJ, Bevova MR, Abbink TE, et al.

Am J Hum Genet. 2013 May 2;92(5):774-80. doi: 10.1016/j.ajhg.2013.04.006.

PubMed [citation]

PMID:: 23643384
PMCID:: PMC3644624

Details of each submission

From OMIM, SCV000071697.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 2 sisters from the United States with hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL; 615281), Taft et al. (2013) identified compound heterozygous mutations in the DARS gene: a c.1379G-A transition in exon 15, resulting in an arg460-to-his (R460H) substitution at a conserved residue, and a c.1480C-T transition in exon 16, resulting in an arg494-to-gly (R494G; 603084.0006) substitution at a conserved residue. Molecular modeling suggested that the R460H mutation may alter an amino acid likely to be fundamental to chains supporting the active site, and that the R494G mutation is likely to destabilize the tRNA-protein interaction. The R460H mutation was not found in several large control databases, while the R494G mutation was found at a frequency of 0.001%.

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

Last Updated: Nov 19, 2022

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