rs1553201258

Variant names:

• chr1-173828312-TT-C
• rs1553201258
• NM_018122.5:c.228-21_228-20delTTinsC

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_018122.5(DARS2):​c.228-21_228-20delTTinsC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: DARS2 NM_018122.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.51

Genes affected

DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-173828312-TT-C is Pathogenic according to our data. Variant chr1-173828312-TT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5	c.228-21_228-20delTTinsC		intron_variant	Intron 2 of 16	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.228-21_228-20delTTinsC		intron_variant	Intron 2 of 15		NP_001352141.1
DARS2	NM_001365213.2	c.228-21_228-20delTTinsC		intron_variant	Intron 2 of 13		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.228-21_228-20delTTinsC		intron_variant	Intron 2 of 16		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes Cov.: 27

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:4

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. -

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 25, 2010

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jan 22, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The c.228-21_228-20delTTinsC variant in DARS2 has been reported in >10 individuals with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 17384640, 18619624, 24566671, 33977142), and segregated with disease in 5 affected relatives from 5 families (PMID: 24566671). Data from large population studies is insufficient to assess the frequency of this variant. This variant has also been reported in ClinVar (Variation ID: 1057) and has been interpreted as Pathogenic by University Medical Centre Ljubljana, GeneReviews, and OMIM. Of the many affected individuals, 5 were compound heterozygotes that carried a reported pathogenic/likely pathogenic variant in trans, which increases the likelihood that the c.228-21_228-20delTTinsC variant is pathogenic (Variation ID: 503692, 102743, 1059; PMID: 17384640, 24566671). In vitro functional studies provide some evidence that the c.228-21_228-20delTTinsC variant may impact protein function (PMID: 24566671). However these types of assays may not accurately represent biological function. cDNA analysis performed shows that the c.228-21_228-20delTTinsC variant is predicted to lead to exon skipping of exon 3, and is predicted to result in nonsense mediated decay (NMD) (PMID: 17384640). Variants that occur in this intron 2 splice region are known to be leaky, which may explain some variability in phenotype (PMID: 24566671). Loss of function of the DASRS2 gene is an established disease mechanism in autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. This variant is located in the intron 2 splice region. This region of DARS2 is an established mutational hotspot and most individuals with LBSL have variants in this region (PMID: 24566671). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome. ACMG/AMP Criteria applied: PM3_very-strong, PP1_strong, PVS1_strong, PS3_moderate, PM1_supporting, PM2_supporting (Richards 2015). -

not provided Pathogenic:2

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the DARS2 gene. It does not directly change the encoded amino acid sequence of the DARS2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with leukoencephalopathy (PMID: 17384640). ClinVar contains an entry for this variant (Variation ID: 1057). Studies have shown that this variant alters DARS2 gene expression (PMID: 22023289). For these reasons, this variant has been classified as Pathogenic. -

Mar 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNA studies demonstrate a damaging effect: skipping of exon 3 particularly in neuronal cells (PMID: 22023289); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 228-20_-21delTTinsC, R76SfsX5; This variant is associated with the following publications: (PMID: 37563224, 24566671, 31912665, 33977142, 33972171, 17384640, 38465286, 22023289, 18619624) -

Clubfoot;C0018099:Gout;C0020538:Hypertensive disorder;C0311394:Difficulty walking;C0338474:CNS demyelination;C1112256:Sensorimotor neuropathy;C1849134:Impaired vibration sensation in the lower limbs;C4025609:EMG: axonal abnormality;C4551583:Cerebral cortical atrophy;C5399834:Abnormal foot morphology Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dysmetria;C0751837:Gait ataxia;C1836150:Gait imbalance Pathogenic:1

Jan 15, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553201258; hg19: chr1-173797450;