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NM_001349.4(DARS1):c.242G>A (p.Arg81His) AND Hypomyelination with brain stem and spinal cord involvement and leg spasticity

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 13, 2017
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:
RCV000578193.2

Allele description [Variation Report for NM_001349.4(DARS1):c.242G>A (p.Arg81His)]

NM_001349.4(DARS1):c.242G>A (p.Arg81His)

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.242G>A (p.Arg81His)
HGVS:
  • NC_000002.12:g.135961474C>T
  • NG_034149.1:g.29211G>A
  • NM_001293312.1:c.-59G>A
  • NM_001349.4:c.242G>AMANE SELECT
  • NP_001340.2:p.Arg81His
  • NC_000002.11:g.136719044C>T
  • NM_001349.2:c.242G>A
Protein change:
R81H
Links:
dbSNP: rs532864330
NCBI 1000 Genomes Browser:
rs532864330
Molecular consequence:
  • NM_001293312.1:c.-59G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001349.4:c.242G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000680030Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Sep 13, 2017) 		unknownclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot provided1not providednot providednot providedclinical testing

Citations

PubMed

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV000680030.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

A heterozygous missense variant, NM_001349.2(DARS):c.242G>A, has been identified in exon 4 of 16 of the DARS gene. This substitution creates a minor amino acid change from an arginine to a histidine at position 81, NP_001340.2(DARS):p.(Arg81His). The arginine residue at this position has very high conservation (100 vertebrates, UCSC). It is located within a oligonucleotide/oligosaccharide-binding fold. In-silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.0004 (0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as a VARIANT of UNKNOWN SIGNIFICANCE (VUS). The presence of these two DARS variants suggests a possible compound heterozygous mode of inheritance which is consistent with hypomyelination with brainstem and spinal cord involvement, and leg spasticity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providedBloodnot providednot providednot provided1not provided

Last Updated: May 7, 2024