1-173831632-T-C

Variant names:

• chr1-173831632-T-C
• rs142433332
• NM_018122.5:c.492+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_018122.5(DARS2):​c.492+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000234 in 1,603,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: DARS2 NM_018122.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 5.46
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.049535602 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 1-173831632-T-C is Pathogenic according to our data. Variant chr1-173831632-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1062.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.492+2T>C		splice_donor_variant, intron_variant	Intron 5 of 16	ENST00000649689.2	NP_060592.2
DARS2	NM_001365212.1	c.492+2T>C		splice_donor_variant, intron_variant	Intron 5 of 15		NP_001352141.1
DARS2	NM_001365213.2	c.492+2T>C		splice_donor_variant, intron_variant	Intron 5 of 13		NP_001352142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS2	ENST00000649689.2	c.492+2T>C		splice_donor_variant, intron_variant	Intron 5 of 16		NM_018122.5	ENSP00000497569.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000331 AC: 83 AN: 251028 AF XY: 0.000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000225 AC: 327 AN: 1451196 Hom.: 0 Cov.: 28 AF XY: 0.000241 AC XY: 174 AN XY: 722742

African (AFR) AF: 0.0000601 AC: 2 AN: 33268

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00169 AC: 90 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.000161 AC: 177 AN: 1102298

Other (OTH) AF: 0.000183 AC: 11 AN: 60040

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74468

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000329 Hom.: 3

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:12 Other:1

May 08, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 25, 2014

Courtagen Diagnostics Laboratory, Courtagen Life Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 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.492+2T>C variant in DARS2 has been reported in >10 individuals with leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (PMID: 34631948, 23652419, 17384640, 24566671, 33977142, 37563224), segregated with disease in 4 affected relatives from 2 families (PMID: 24566671, 34631948), and has been identified in 0.2% (51/29558) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142433332). 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: 1062) and has been interpreted as pathogenic by multiple submitters. Of the many affected individuals, >10 were compound heterozygotes that carried a reported pathogenic variant with unknown phase (Variation ID: 1057; PMID: 2456667, 17384640, 23652419, 34631948), which increases the likelihood that the c.492+2T>C variant is pathogenic. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not enough to determine/rule out pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. 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, PVS1_moderate, PP1 (Richards 2015). -

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

Nov 22, 2019

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. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Apr 15, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 15, 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.492+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00033 in 251028 control chromosomes in the gnomAD database, predominantly at a frequency of ~0.002 and ~0.0016 within the Ashkenazi Jewish and Finnish European subpopulations, respectively; however, despite the relatively high frequency, no homozygous occurrences were reported. The carrier frequency of the 492+2T>C variant among Finnish healthy controls was reported to be 1 in 380 in a population-based study (Isohanni_2010), which is mostly consistent with the gnomAD data. On the other hand, the variant c.492+2T>C, has been reported in the literature in several compound heterozygous individuals affected with Leukoencephalopathy with Brain Stem and Spinal Cord Involvement-High Lactate Syndrome (e.g. Scheper_2007, Isohanni_2010, Stellingwerff_2021, Yepez_2022). In addition, some of these studies noted that aberrant splicing was detected with cDNA analysis, resulting in an in-frame deletion of exon 5, which was described as M134_K165del or Lys133_Lys164del at the protein level (Scheper_2007, Yepez_2022). Since no homozygous patients were reported, this suggests that homozygosity for the variant might be embryonic lethal or manifests as a different, yet unidentified phenotype (Isohanni_2010). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DARS2 c.492+2T>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in at least seven studies, in which it was found in a compound heterozygous state in a total of 22 patients with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, 17 of whom carried the c.492+2T>C variant in trans with the most common pathogenic DARS2 variant (Scheper et al. 2007; Isohanni et al. 2010; Steenweg et al. 2012; Moore et al. 2012, Martikainen et al. 2013; Alibas et al. 2014; Tylki-Szymanska et al. 2014). Based on in silico analysis, the c.492+2T>C variant is predicted to affect splicing of intron five and cause exon skipping (Scheper et al. 2007; Martikainen et al. 2013). The variant was identified in two out of 575 control subjects in a heterozygous state (Scheper et al. 2007; Isohanni et al. 2010) and is reported at a frequency of 0.00136 in the European (Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the c.492+2T>C variant is classified as pathogenic for leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.038%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001062 /PMID: 17384640). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:6

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 5 of the DARS2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DARS2 are known to be pathogenic (PMID: 17384640, 24566671). This variant is present in population databases (rs142433332, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (PMID: 17384640). ClinVar contains an entry for this variant (Variation ID: 1062). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DARS2: PVS1, PS4:Moderate -

Nov 02, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24005482, 20506600, 35379322, 25525159, 17384640, 24558666, 24407472, 29915382, 23065766, 22843165, 34426522, 31589614, 23652419, 19592391, 33977142) -

May 05, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3, PS4_moderate, PVS1 -

Aug 08, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 04, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.492+2T>C intronic alteration consists of a T to C substitution two nucleotides after Intron 5 (C) of the DARS2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the C allele has an overall frequency of 0.04% (107/282438) total alleles studied. The highest observed frequency was 0.22% (23/10360) of Ashkenazi Jewish alleles. This alteration has been detected in conjunction with other DARS2 alterations in multiple unrelated individuals with mitochondrial aspartyl-tRNA synthetase deficiency (Stellingwerff, 2021; Scheper, 2007). This nucleotide position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is deleterious. The variant is significantly destabilizing to the structure of a necessary domain. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		5.5
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs142433332; hg19: chr1-173800770; COSMIC: COSV53405515;