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.

Biomedical Research and Study Center Riga Latvia

Central Clinical Hospital of Ministry of the Interior and Administration in Warsaw Warsaw Poland

Centre of Molecular Biology And Genetics University Hospital Brno Czech Republic

Clinical Institute of Medical Genetics University Medical Centre Ljubljana Ljubljana Slovenia

Department of Biology and Microbiology Riga Stradins University Riga Latvia

Department of Clinical Genetics Institute of Clinical Medicine University of Tartu Tartu Estonia

Department of Clinical Genetics United Laboratories Tartu University Hospital Tartu Estonia

Department of Hematology Transplantation and Internal Medicine University Clinical Center of the Medical University of Warsaw Warsaw Poland

Department of Human and Medical Genetics Institute of Biomedical Sciences Faculty of Medicine Vilnius University Vilnius Lithuania

Department of Neurology Amsterdam University Medical Centre Amsterdam Neuroscience Amsterdam The Netherlands

Department of Neurology and Neurophysiology Balgrist University Hospital University of Zurich Zürich Switzerland

Department of Neurology Erasmus MC University Medical Center Rotterdam The Netherlands

Department of Neurology University Medical Centre Ljubljana Faculty of Medicine University of Ljubljana Ljubljana Slovenia

Institute of Molecular Genetics of National Research Centre Kurchatov Institute Moscow Russia

Medical Genetics Clinic Children's Clinical University Hospital Riga Latvia

MNM Diagnostics Sp z o o Poznań Poland

Rare Disease Center Riga East Clinical University Hospital Riga Latvia

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$a CAPN3 c.1746-20C>G variant is hypomorphic for LGMD R1 calpain 3-related / $c M. Mroczek, I. Inashkina, J. Stavusis, P. Zayakin, A. Khrunin, I. Micule, V. Kenina, A. Zdanovica, J. Zídková, L. Fajkusová, S. Limborska, AJ. van der Kooi, E. Brusse, L. Leonardis, A. Maver, S. Pajusalu, K. Õunap, S. Puusepp, P. Dobosz, M. Sypniewski, B. Burnyte, B. Lace

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$a 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.

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