ClinVar Miner

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

gnomAD frequency: 0.00548  dbSNP: rs201892814
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000078089 SCV000109927 likely benign not specified 2016-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000585323 SCV000568286 likely benign not provided 2018-06-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18055493, 28877744, 20635405, 17994539, 17979987, 17157502, 16141003, 16411092, 15351423, 16372320, 27447704, 27708273, 26886200, 27884173, 26301378, 28602176, 25135358, 18854869, 30028523, 30919934, 31788660, 32403337, 31127727)
Invitae RCV000559180 SCV000645480 benign Autosomal recessive limb-girdle muscular dystrophy type 2A 2021-12-18 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000585323 SCV000692807 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626578 SCV000747279 pathogenic Elevated circulating creatine kinase concentration; 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 Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-12-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000078089 SCV002074538 benign not specified 2022-01-06 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.1746-20C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. This is confirmed by one study reporting no impact on splicing (example, Krahn_2007). In another study. the average value for amount of CAPN3 transcripts relative to three housekeeping genes using CAPN3 mRNA of a patient without splice variant as calibrator, showed the levels of transcript in a patient with this variant in a compound heterozygous genotype did not differ significantly from the control values (example, Stehlikova_2007). The variant allele was found at a frequency of 0.0031 in 251486 control chromosomes, predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This variant is among those re-classified as benign based on lack of phenotype in homozygotes (ACMG BS2-only variants) (example, Abouelhoda_2016). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1746-20C>G has been reported in the literature as a non-informative genotype in numerous compound heterozygous patients undergoing testing for limb girdle muscular dystrophy via panel/exome/single gene analysis (example, Piluso_2005, Krahn_2007, Stehlikova_2007, Nascimbeni_2010, Avila_2015, Harris_2017, Reddy_2017). In at-least one of these reports it was found to co-occur in cis with a different allele (c.1745+4_1745+7delAGTG) that was characterized by complementary DNA analysis as having a pathogenic outcome (example, Krahn_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy type 2A, Autosomal Recessive. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign.
Natera, Inc. RCV000559180 SCV001460840 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-04-17 no assertion criteria provided clinical testing

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