ClinVar

Description

Variant summary: LARS c.245A>G (p.Lys82Arg) results in a conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain (IPR002300) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0049 in 251424 control chromosomes in the gnomAD database, including 4 homozygotes. The observed variant frequency is approximately 4.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in LARS causing Liver Failure Acute Infantile, Type 1 phenotype (0.0011), strongly suggesting that the variant is benign. c.245A>G was initially reported in the literature to co-segregate along with another LARS1 variant, c.1118A>G (p.Tyr373Cys) among all affected individuals from a single consanguineous Irish Traveller family with Infantile Hepatopathy (example, Casey_2012). This report(s) does not provide unequivocal conclusions about association of the variant with Liver Failure Acute Infantile, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 benign. Based on the evidence outlined above, the variant was classified as benign.