Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

MARS1 – Charcot-Marie-Tooth disease, axonal, type 2U

Methionyl-tRNA synthetase (MARS1) has been implicated in autosomal dominant Charcot-Marie-Tooth disease, axonal, type 2U (CMT2U). To date, two unrelated probands harboring heterozygous MARS1 missense variants—c.1852C>T (p.Arg618Cys) and c.1189G>A (p.Ala397Thr)—have been reported in association with early-onset axonal sensorimotor neuropathy (PMID:29655802; PMID:31356216). Both variants affect highly conserved residues within the catalytic core and were absent from population databases.

Functional yeast complementation and structural modeling confirm that p.Arg618Cys and p.Ala397Thr impair MetRS function and recapitulate neuropathic phenotypes in vivo (PMID:29655802; PMID:31356216). No additional segregation beyond the proband has been documented. Overall, current evidence supports a limited but credible association, justifying inclusion of MARS1 in genetic testing panels for CMT2U.

References

  • European journal of medical genetics | 2018 | MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease. PMID:29655802
  • Journal of neuromuscular diseases | 2019 | A Novel Mutation in MARS in a Patient with Charcot-Marie-Tooth Disease, Axonal, Type 2U with Congenital Onset. PMID:31356216

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

2 unrelated probands with autosomal dominant heterozygous MARS1 variants and limited segregation ([PMID:29655802]; [PMID:31356216])

Genetic Evidence

Limited

Two heterozygous variants identified in independent CMT2U probands; no additional familial segregation

Functional Evidence

Moderate

Yeast complementation assays and structural modeling demonstrate pathogenicity of p.Ala397Thr and p.Arg618Cys variants ([PMID:31356216]; [PMID:29655802])