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 literature predicts a toxic gain-of-function mechanism for CMTDIC: heterozygous YARS1 variants acquire neomorphic properties, an aberrant conformational opening, axonal mislocalization, and novel interactions demonstrated in Drosophila and yeast models, that damage peripheral axons beyond any loss of aminoacylation. Because loss of catalytic activity is necessary but not sufficient and the toxicity is intrinsic to the mutant, the evidence supports a neomorphic gain rather than haploinsufficiency, holding confidence at medium.

Rationale:
Heterozygous YARS1 alleles acquire an aberrant open conformation and novel interactions, with wild-type failing to rescue and toxicity dissociable from aminoacylation loss, pointing to a toxic neomorphic gain rather than disruption of wild-type. Because the precise neomorphic partner and the residual role of catalytic loss remain debated, confidence holds at medium.

ClinVar Pathogenic Variants

View CMTDIC ClinVar Variants

ClinGen Curation

View YARS1 ClinGen Curation

CMTDIC OMIM Entry

CMTDIC OMIM

YARS1 OMIM Entry

YARS1 OMIM