ClinVar Miner

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

dbSNP: rs1595834751
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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 Omics RCV003145204 SCV003828926 uncertain significance not provided 2020-10-07 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003392624 SCV004121413 uncertain significance CAPN3-related condition 2022-08-18 criteria provided, single submitter 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. 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.
Natera, Inc. RCV000820146 SCV002085506 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-03-23 no assertion criteria provided clinical testing

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