CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related

Hum Mutat. 2022 Oct;43(10):1347-1353. doi: 10.1002/humu.24421. Epub 2022 Jun 22.


The investigated intronic CAPN3 variant NM_000070.3:c.1746-20C>G occurs in the Central and Eastern Europe with a frequency of >1% and there are conflicting interpretations on its pathogenicity. We collected data on 14 patients carrying the CAPN3 c.1746-20C>G variant in trans position with another CAPN3 pathogenic/likely pathogenic variant. The patients compound heterozygous for the CAPN3 c.1746-20C>G variant presented a phenotype consistent with calpainopathy of mild/medium severity. This variant is most frequent in the North/West regions of Russia and may originate from that area. Molecular studies revealed that different splicing isoforms are produced in the muscle. We hypothesize that c.1746-20C>G is a hypomorphic variant with a reduction of RNA and protein expression and only individuals having a higher ratio of abnormal isoforms are affected. Reclassification of the CAPN3 variant c.1746-20C>G from variant with a conflicting interpretation of pathogenicity to hypomorphic variant explains many unidentified cases of limb girdle muscular dystrophy R1 calpain 3-related in Eastern and Central Europe.

Keywords: CAPN3; LGMD; LGMD R1 calpain 3-related; calpainopathy; hypomorphic variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calpain* / genetics
  • Humans
  • Muscle Proteins* / genetics
  • Muscular Dystrophies, Limb-Girdle* / genetics
  • Mutation
  • RNA Splicing


  • Muscle Proteins
  • CAPN3 protein, human
  • Calpain