Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes

Hum Mutat. 2022 Jul;43(7):869-876. doi: 10.1002/humu.24372. Epub 2022 Apr 21.


Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot-Marie-Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41-year-old man with CMT2D. Functional studies using yeast complementation assays support a loss-of-function effect for both variants; however, this did not reveal variable effects that might explain the phenotypic differences. These cases expand the mutational spectrum of GARS1-related disorders and demonstrate phenotypic variability based on the specific substitution at a single residue.

Keywords: Charcot−Marie−Tooth disease; GARS1; complementation assay; missense variant; spinal muscular atrophy.

Publication types

  • Case Reports

MeSH terms

  • Charcot-Marie-Tooth Disease* / genetics
  • Codon
  • Glycine-tRNA Ligase* / genetics
  • Humans
  • Mutation
  • Phenotype


  • Codon
  • Glycine-tRNA Ligase

Supplementary concepts

  • Charcot-Marie-Tooth disease, Type 2D