ClinVar

Description

Variant summary: EARS2 c.1547G>A (p.Arg516Gln) results in a conservative amino acid change located in the Aminoacyl-tRNA synthetase, class I, anticodon-binding domain (IPR045462) 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 6.4e-05 in 249576 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547G>A has been reported in the literature in compound heterozygous individuals affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (e.g., Steenweg_2012, Roux_2021). These data indicate that the variant may 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: 33128823, 33972171, 22492562). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic (n = 1) or likely pathogenic (n = 2). Additionally, another missense variant affecting the same amino acid, c.1546C>T (p.Arg516Trp), has been reported in the literature in patients affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (PMID: 27206875). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.