NM_018122.5:c.1876C>G

Variant names:

• chr1-173857643-C-G
• rs121918205
• NM_018122.5:c.1876C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_018122.5(DARS2):​c.1876C>G​(p.Leu626Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L626Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DARS2 NM_018122.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.35

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-173857644-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1067.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 1-173857643-C-G is Pathogenic according to our data. Variant chr1-173857643-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1058.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5	c.1876C>G	p.Leu626Val	missense_variant	Exon 17 of 17	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.1723C>G	p.Leu575Val	missense_variant	Exon 16 of 16		NP_001352141.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.1876C>G	p.Leu626Val	missense_variant	Exon 17 of 17		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:1 Uncertain:1

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 22, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu626Val variant in DARS2 has been reported in 2 individuals with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 17384640, 24566671), and has been identified in 0.0003% (4/1180012) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918205). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1058) and has been interpreted as pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Leu626Val variant may slightly impact protein function (PMID: 17384640). However, these types of assays may not accurately represent biological function. Computational tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PS3_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.8	M;.;.;M;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.7	N;.;.;.;.
REVEL	Pathogenic	0.76
Sift	Benign	0.12	T;.;.;.;.
Sift4G	Uncertain	0.040	D;.;.;.;.
Polyphen		0.95	P;.;.;P;.
Vest4		0.83
MutPred		0.88		Gain of methylation at K627 (P = 0.1216);.;.;Gain of methylation at K627 (P = 0.1216);.;
MVP		0.92
MPC		0.75
ClinPred		0.91	D
GERP RS		1.2
Varity_R		0.38
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918205; hg19: chr1-173826781;