chr1-173831593-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_018122.5(DARS2):c.455G>T(p.Cys152Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,613,926 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 (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DARS2
NM_018122.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 6.17

Variant links:

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]

DARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

PP5

Variant 1-173831593-G-T is Pathogenic according to our data. Variant chr1-173831593-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-173831593-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS2	NM_018122.5 link	c.455G>T	p.Cys152Phe	missense_variant	Exon 5 of 17	ENST00000649689.2	NP_060592.2	Q6PI48Q9H9J7
DARS2	NM_001365212.1 link	c.455G>T	p.Cys152Phe	missense_variant	Exon 5 of 16		NP_001352141.1
DARS2	NM_001365213.2 link	c.455G>T	p.Cys152Phe	missense_variant	Exon 5 of 14		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2 link	c.455G>T	p.Cys152Phe	missense_variant	Exon 5 of 17		NM_018122.5	ENSP00000497569.1		Q6PI48

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251326

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

157

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000137

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000233

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:4Other:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Cys152Phe variant in DARS2 has been reported in >10 individuals with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 24566671, 17384640, 19592391, 23065766), segregated with disease in 2 affected relatives from 2 families (PMID: 17384640, 24566671), and has been identified in 0.01% (167/1179920) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918208). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 1061) and has been interpreted as Pathogenic by multiple submitters. Of the many affected individuals, >10 were compound heterozygotes that carried a reported pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Cys152Phe variant is pathogenic (Variation ID: 1061; PMID: 24566671, 17384640, 19592391, 23065766). In vitro functional studies provide some evidence that the p.Cys152Phe variant may slightly impact protein function (PMID: 23216004). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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, PP3, PS3_supporting (Richards 2015). -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Several individuals share haplotypes involving five or six microsatellite markers on chromosome 1p25. The pathogenic variants 492+2T>C and 455G>T are correlated with two of these haplotypes and are often seen in affected individuals of northeastern European origin. -

Jun 03, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DARS2 c.455G>T (p.Cys152Phe) results in a non-conservative amino acid change located in the dimerization interface (van Berge_2013) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251326 control chromosomes. This frequency does not allow conclusions about variant significance. c.455G>T has been reported in the literature in multiple individuals affected with Leukoencephalopathy With Brain Stem And Spinal Cord Involvement-High Lactate Syndrome (example, Isohanni_2010, Steenweg_2012, van Berge_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced protein levels, decreased stability (approximately 50% of WT), decreased dimerization to WT and/or to the same or another mutation (approximately 30% of WT). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:4

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with reduced protein expression and dimerization (PMID: 23216004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17384640, 29147736, 34426522, 31589614, 33686843, 31980526, 30325133, 24566671, 37563224, 23216004, 38790244, 38125072) -

Dec 06, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 152 of the DARS2 protein (p.Cys152Phe). This variant is present in population databases (rs121918208, gnomAD 0.03%). This missense change has been observed in individuals with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (PMID: 17384640, 24566671). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1061). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DARS2 protein function. Experimental studies have shown that this missense change affects DARS2 function (PMID: 23216004). For these reasons, this variant has been classified as Pathogenic. -

DARS2-related disorder

Pathogenic:1

Jan 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DARS2 c.455G>T variant is predicted to result in the amino acid substitution p.Cys152Phe. This variant has been reported in individuals with autosomal recessive leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) (Scheper et al. 2007. PubMed ID: 17384640; van Berge et al. 2014. PubMed ID: 24566671, supplementary table 3). A functional study shows that this variant leads to reduced levels of the encoded protein (mitochondrial aspartyl-tRNA synthetase and dimerization) (van Berge et al. 2013. PubMed ID: 23216004). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

See cases

Pathogenic:1

May 16, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PM2,PP1,PP3,PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;.;.;.;T;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D;D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.00010

MutationAssessor

Uncertain

2.9

M;.;.;.;M;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.8

D;.;.;.;.;.;.

REVEL

Pathogenic

0.71

Sift

Uncertain

0.010

D;.;.;.;.;.;.

Sift4G

Uncertain

0.0050

D;.;.;.;.;.;.

Polyphen

0.94

P;.;.;.;P;.;.

Vest4

0.94

MVP

0.96

MPC

0.68

ClinPred

0.83

GERP RS

6.1

Varity_R

0.84

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over