rs1553201258

chr1-173828311-TTT-TC

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_228-20delinsC 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:6
• 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/exons	MANE	UniProt
DARS2	NM_018122.5	c.228-21_228-20delinsC		intron_variant		ENST00000649689.2
DARS2	NM_001365212.1	c.228-21_228-20delinsC		intron_variant
DARS2	NM_001365213.2	c.228-21_228-20delinsC		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS2	ENST00000649689.2	c.228-21_228-20delinsC		intron_variant			NM_018122.5	P1

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	May 25, 2010	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2010	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2023

Published functional studies demonstrate a damaging effect in neuronal cell line SH-SY5Y (vanBerge et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as 228-20_-21delTTinsC, R76SfsX5; This variant is associated with the following publications: (PMID: 24566671, 31912665, 33977142, 18619624, 33972171, 17384640, 22023289) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 15, 2015

- -

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;