ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1327T>C (p.Ser443Pro)

dbSNP: rs1595834751
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
Labcorp Genetics (formerly Invitae), Labcorp RCV000820146 SCV000960844 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 443 of the CAPN3 protein (p.Ser443Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 32896923; Invitae). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 26810512); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 662490). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV003145204 SCV003828926 uncertain significance not provided 2020-10-07 criteria provided, single submitter clinical testing
Natera, Inc. RCV000820146 SCV002085506 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-03-23 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004538126 SCV004121413 uncertain significance CAPN3-related disorder 2024-01-05 no assertion criteria provided clinical testing The CAPN3 c.1327T>C variant is predicted to result in the amino acid substitution p.Ser443Pro. This variant was reported to segregate in four family members with autosomal dominant limb girdle muscular dystrophy (Family 6, Gonzalez-Mera et al. 2020. PubMed ID: 32896923) and in a patient with rhabdomyolysis and muscular dystrophy (Patient 5, Lahoria et al 2016. PubMed ID: 26810512). The patient reported in Lahoria et al. also had a second variant in CAPN3; however, phase was not noted. At PreventionGenetics, we have observed this variant in the heterozygous state in a patient sent for limb girdle muscular dystrophy testing; however, additional segregation analysis was not performed (internal data). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, another variant impacting the same amino acid residue (p.Ser443Phe) has also been reported in patients with limb-gridle muscular dystrophy (Patient 6, Luo et al. 2012. PubMed ID: 22926650). Although we suspect that the c.1327T>C (p.Ser443Pro) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.