CMTDIC

Genetic Context

HGNC-Approved Gene Symbol

YARS1

Gene Full Name

tyrosyl-tRNA synthetase 1

HGNC Gene Alias(es)

YTS, YARS, YRS, tyrRS

Chromosome

1p35.1

Zygosity of Responsible Variant

Heterozygous

Mitochondrial Involvement

No

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
Medium

Prediction:
The evidence supports a neomorphic gain-of-function mechanism for CMTDIC: the dominant YARS1 alleles G41R, E196K, and the 153-156 VKQV deletion loosen the tyrosyl-tRNA synthetase into a conformation that mislocalizes within axons and acquires binding partners the normal enzyme does not engage, as demonstrated in Drosophila and yeast. Because reduced aminoacylation is necessary but not sufficient for the phenotype in those models, and because the toxicity travels with the mutant protein, the evidence favors a new activity over a diminished enzyme supply.

Rationale:
Toxicity here is dissociable from catalysis, since the mutant enzyme damages axons in fly and yeast models in ways that reduced aminoacylation alone does not account for, and added wild-type YARS1 does not correct the phenotype. Which partners the mislocalized enzyme engages, and how much the residual catalytic deficit contributes, both remain open, so the grade is medium.

ClinVar Pathogenic Variants

View YARS1 ClinVar Variants

ClinGen Curation

View YARS1 ClinGen Curation

CMTDIC OMIM Entry

CMTDIC OMIM

YARS1 OMIM Entry

YARS1 OMIM