ClinVar Genomic variation as it relates to human health

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 108 of the EARS2 protein (p.Arg108Trp). This variant is present in population databases (rs376103091, gnomAD 0.03%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22492562, 26893310). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 39787). 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 EARS2 protein function.

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: 27571996, 27875839, 33855712, 33972171, 22492562, 26893310, 25058219, 27374853, 31520968, 34440436)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039787). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 22492562). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

The missense variant c.322C>T (p.Arg108Trp) in the EARS2 gene has been reported previously in heterozygous and compound heterozygous state in individuals affected with Leukoencephalopathy. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (Steenweg et al., 2012; Taskin et al., 2016) Missense changes are a common disease-causing mechanism. This variant is reported with the allele frequency (0.01%) in the gnomAD and novel (not in any individuals) in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/ Pathogenic (Multiple Submissions). The amino acid Arginine at position 108 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg108Trp in EARS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Variant summary: EARS2 c.322C>T (p.Arg108Trp) results in a non-conservative amino acid change located in the glutamyl/glutaminyl-tRNA synthetase, class Ib, catalytic domain (IPR020058) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 231208 control chromosomes. c.322C>T has been reported in the literature in multiple individuals affected with and/or with clinical features of Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (e.g. Steenweg_2012, Taylor_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22492562, 25058219). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.