chr1-173831593-G-T
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
Consequence
NM_018122.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DARS2 | NM_018122.5 | c.455G>T | p.Cys152Phe | missense_variant | Exon 5 of 17 | ENST00000649689.2 | NP_060592.2 | |
DARS2 | NM_001365212.1 | c.455G>T | p.Cys152Phe | missense_variant | Exon 5 of 16 | NP_001352141.1 | ||
DARS2 | NM_001365213.2 | c.455G>T | p.Cys152Phe | missense_variant | Exon 5 of 14 | NP_001352142.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251326Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135876
GnomAD4 exome AF: 0.000107 AC: 157AN: 1461718Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79AN XY: 727172
GnomAD4 genome AF: 0.000105 AC: 16AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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) -
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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. -
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Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome Pathogenic:3Other:1
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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. -
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. -
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DARS2-related disorder Pathogenic:1
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
ACMG categories: PS3,PM2,PP1,PP3,PP5 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at