CAPN3 c.1746‐20C>G variant is hypomorphic for LGMD R1 calpain 3‐related. Issue 10 (22nd June 2022)

• Record Type: Journal Article
• Authors: Mroczek, Magdalena; Inashkina, Inna; Stavusis, Janis; Zayakin, Pawel; Khrunin, Andrey; Micule, Ieva; Kenina, Victorija; Zdanovica, Anna; Zídková, Jana; Fajkusová, Lenka; Limborska, Svetlana; van der Kooi, Anneke J.; Brusse, Esther; Leonardis, Lea; Maver, Ales; Pajusalu, Sander; Õunap, Katrin; Puusepp, Sanna; Dobosz, Paula; Sypniewski, Mateusz; Burnyte, Birute; Lace, Baiba
• Is Part Of: Human mutation. Volume 43:Issue 10(2022)
• Page Start: 1347
• Page End: 1353
• Publication Date: 2022-06-22
• Subjects: calpainopathy -- CAPN3 -- hypomorphic variant -- LGMD -- LGMD R1 calpain 3‐related; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24421
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: 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. Abstract : Variant c.1746‐20C>G is a hypomorphic allele, associated with LGMD R1 calpain3‐related.