ClinVar Genomic variation as it relates to human health

Likely pathogenicity based on finding it twice in our laboratory in trans with another variant in individuals with liver dysfunction, anemia, IUGR, heart defects. Heterozygotes would be expected to be asymptomatic carriers.

This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Variant summary: LARS1 c.1292T>A (p.Val431Asp) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 282514 control chromosomes. c.1292T>A has been reported in the literature in individuals affected with Liver Failure Acute Infantile, Type 1. 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=1, likely pathogenic n=2, VUS n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This variant has been previously reported as a compound heterozygous change in patients with infantile liver failure syndrome 1 (PMID: 30349989, 32699352). Functional studies showed that the presence of the c.1292T>A (p.Val431Asp) variant, with another LARS pathogenic variant in trans, resulted in reduced protein levels (PMID: 32699352, 34194004). The c.1292T>A (p.Val431Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (98/282514), and is absent in the homozygous state. Based on the available evidence, the c.1292T>A (p.Val431Asp) variant is classified as Likely Pathogenic.

The LARS1 c.1292T>A variant is predicted to result in the amino acid substitution p.Val431Asp. This variant has been reported in multiple unrelated individuals with infantile liver failure syndrome (Peroutka et al. 2019. PubMed ID: 30349989; Lenz et al. 2020. PubMed ID: 32699352; Hegarty et al. 2021. PubMed ID: 34023347). Although this variant was not examined directly, studies of patient derived fibroblasts, compound heterozygous for this variant and a splice variant (c.1503+3A>G), found decreased aminoacylation activity suggesting this variant impacts protein function (Kok et al. 2021. PubMed ID: 34194004). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-145531558-A-T). This variant is interpreted as likely pathogenic.

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 LARS protein function. ClinVar contains an entry for this variant (Variation ID: 431849). This missense change has been observed in individuals with acute infantile liver failure (PMID: 30349989, 32699352). This variant is present in population databases (rs150429680, gnomAD 0.06%). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 431 of the LARS protein (p.Val431Asp).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with infantile liver failure syndrome 1 (MIM#615438). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated LARS1 editing domain (PMID: 30349989, 25051973). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed as compound heterozgous in at least nine individuals with infantile liver failure syndrome 1 (MIM#615438) (ClinVar, PMIDs: 30349989, 34023347, 34194004, 32699352). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies on fibroblasts from patients with this variant have shown decreased LARS1 enzyme activity and decreased protein expression (PMIDs: 34194004, 32699352). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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: 25326635, 30349989, 34023347, 32699352, 25051973, 34194004, 33726816, 37269902, 36135330, 37432431)