ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1543G>A (p.Gly515Arg)

gnomAD frequency: 0.00034  dbSNP: rs150226817
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Preventiongenetics, part of Exact Sciences RCV000245397 SCV000301870 likely benign not specified criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000724737 SCV000331893 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000245397 SCV000612636 uncertain significance not specified 2016-12-31 criteria provided, single submitter clinical testing
Invitae RCV000692602 SCV000820432 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 515 of the CAPN3 protein (p.Gly515Arg). This variant is present in population databases (rs150226817, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 254861). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV000724737 SCV001247172 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000724737 SCV002526479 uncertain significance not provided 2021-12-14 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33250842)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000245397 SCV002547801 likely benign not specified 2022-05-27 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.1543G>A (p.Gly515Arg) results in a non-conservative amino acid change located in the subdomain III (IPR033883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 150922 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0011 including 1 homozygote (in the gnomAD database, v3.1 genomes dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no clear conclusions about variant significance. The variant, c.1543G>A, has been reported in the literature in an individual affected with proximal myopathy, who also carried a (likely) pathogenic CAPN3 variant, however the phase of these two variants was not determined (Chakravorty_2020). On the other hand, the variant was also reported in 3 individuals affected with limb-girdle muscular dystrophy (LGMD), however, two of these patients also carried two co-occurring pathogenic variants in other genes, which could explain the phenotype, while the 3rd patient carried a potentially pathogenic CAPN3 variant in cis (LOVD, PMID 30564623). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity Omics RCV000724737 SCV003830575 uncertain significance not provided 2021-11-02 criteria provided, single submitter clinical testing
Natera, Inc. RCV000692602 SCV001460837 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-04-17 no assertion criteria provided clinical testing

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.