ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1303G>A (p.Glu435Lys) (rs149914792)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000440492 SCV000333467 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000440492 SCV000520879 likely pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing A published E435K variant that is likely pathogenic has been identified in the CAPN3 gene. The E435K variant has been reported previously, without a second identifiable CAPN3 variant, in an individual with late onset limb girdle muscular dystrophy (LGMD) who had complete calpain-3 deficiency on Western blot (Fanin et al., 2004). The E435K was subsequently reported in the compound heterozygous state in individuals with LGMD2A (Piluso et al., 2005; Nascimbeni et al., 2010). The E435K variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The E435K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with LGMD (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000820741 SCV000961467 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 435 of the CAPN3 protein (p.Glu435Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs149914792, ExAC 0.02%). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18854869, 20635405). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 282173). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Athena Diagnostics Inc RCV000440492 SCV001143415 likely pathogenic not provided 2019-05-03 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive. Inconclusive segregation with disease.
Nilou-Genome Lab RCV000820741 SCV001653420 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2021-05-18 criteria provided, single submitter 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.