ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.146G>A (p.Arg49His) (rs863224958)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201045 SCV000255654 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2015-08-27 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000201045 SCV001164521 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2018-12-03 criteria provided, single submitter research The homozygous p.Arg49His variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg49His variant in CAPN3 has been reported in the compound heterozygous state in 5 individuals with LGMD (PMID: 17318636, 16650086, 16100770, 16411092). The presence of this variant in combination with multiple CAPN3 variants (1 reported pathogenic, 2 reported VUS, and 2 loss of function variants not reported in ClinVar) and in 5 individuals with LGMD increases the likelihood that the p.Arg49His variant is pathogenic. Another missense variant at the same position, p.Arg49Cys, has been reported likely pathogenic in ClinVar (Variation ID: 193037). This raises the possibility that a change at this position would not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Strong, PM4_Supporting (Richards 2015).
Invitae RCV000201045 SCV001405410 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 49 of the CAPN3 protein (p.Arg49His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another CAPN3 variant in several individuals affected with limb-girdle muscular dystrophy (PMID: 16650086, 17318636, 25135358, Invitae). ClinVar contains an entry for this variant (Variation ID: 217151). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Arg49 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18055493, 18334579, 19285864, 19556129). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000201045 SCV000797544 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2018-01-31 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.