ClinVar Genomic variation as it relates to human health

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

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.

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). Advanced 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 at Invitae 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.

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)

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.

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.