ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1746-20C>G (rs201892814)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585323 SCV000692807 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626578 SCV000747279 pathogenic Elevated serum creatine phosphokinase; Migraine; Difficulty walking; Positive Romberg sign; Paresthesia; EMG: neuropathic changes; Progressive spinal muscular atrophy; Absent muscle fiber calpain-3 2017-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000559180 SCV000796481 uncertain significance Limb-girdle muscular dystrophy, type 2A 2017-12-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078089 SCV000109927 likely benign not specified 2016-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000078089 SCV000568286 uncertain significance not specified 2017-10-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CAPN3 gene. The c.1746-20 C>G variant has been reported multiple times in association with LGMD2A (Aartsma-Rus et al., 2006; Balci et al., 2006; Guglieri et al., 2008; Piluso et al., 2005). However, conflicting evidence has been reported regarding the effect of this variant on splicing and RNA expression. Specifically, Krahn et al. (2007) reported no splicing abnormalities by cDNA analysis of a muscle biopsy from a patient with c.1746-20 C>G and a pathogenic variant, but Western blot analysis showed reduced protein expression. However, Nascimbeni et al. (2010) reported that c.1746-20 C>G altered both RNA splicing by cDNA analysis and protein expression by Western blot in an individual who was compound heterozygous for this variant and a pathogenic variant. The NHLBI Exome Sequencing Project reports c.1746-20 C>G was observed in 33/8598 (0.4%) alleles from individuals of European background, and the 1000 Genomes Project reports it was not observed with any significant frequency. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000559180 SCV000645480 uncertain significance Limb-girdle muscular dystrophy, type 2A 2018-04-09 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. This variant is present in population databases (rs201892814, ExAC 1.0%). This variant has been reported in the compound heterozygous state in individuals affected with limb-girdle muscular dystrophy type 2A (PMID: 16141003, 17157502, 25135358, 26886200, 27708273, 27447704, 18854869). ClinVar contains an entry for this variant (Variation ID: 92408). While some experimental studies on this variant have reported that it does not alter splicing (PMID: 17979987) or CAPN3 mRNA levels (PMID: 17157502), a different study has reported that it leads to aberrant splice isoforms that are predicted to produce non-functional CAPN3 protein (PMID: 20635405). In summary, this is an intronic change with uncertain impact on splicing that has been reported in the general population at relatively high frequency and in individuals affected with CAPN3-related disease. It has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.