Submissions for variant NM_000070.3(CAPN3):c.1342C>T (p.Arg448Cys)

gnomAD frequency: 0.00001  dbSNP: rs776043976

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000291465	SCV000329778	pathogenic	not provided	2023-07-12	criteria provided, single submitter	clinical testing	Published functional studies indicate that R448C results in absent calpain enzyme activity (Fanin et al., 2004; Milic et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16141003, 17994539, 17897828, 15725583, 10330340, 16650086, 18854869, 21670566, 17318636, 31407473, 31589614, 35239206, 32528171, 26404900, 15689361, 31555977, 27447704, 30564623, 17236769, 15221789)
Eurofins Ntd Llc (ga)	RCV000291465	SCV000335221	pathogenic	not provided	2018-02-11	criteria provided, single submitter	clinical testing
Invitae	RCV000274198	SCV000645470	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 448 of the CAPN3 protein (p.Arg448Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 10330340, 16141003, 16650086, 17318636, 18854869, 26404900, 27447704). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 280038). 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%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 15221789, 17236769). This variant disrupts the p.Arg448 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10330340, 15221789, 16141003, 20635405, 21624972, 25135358). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000274198	SCV001164512	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The homozygous p.Arg448Cys variant in CAPN3 was identified by our study in one individual with Limb-Girdle Muscular Dystrophy (LGMD). This variant has been identified in 0.007057% (1/14170) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776043976). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with muscle biopsy specimens from patients with LGMD and the variant provide some evidence that the p.Arg448Cys variant may impact protein function by lowering calpain-3 protein levels and reducing protein activity (PMID: 17236769, 15221789). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. This variant impacts the same residue as the pathogenic p.Arg448His variant, supporting the possibility that a missense mutation at this position may not be tolerated. Many individuals with LGMD and this variant in either the homozygous or compound heterozygous state have been reported in the literature (PMID: 17236769, 15221789, 18854869, 27447704) and this variant has also been reported pathogenic in ClinVar (Variation ID: 280038). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and evidence from in vitro functional studies with muscle biopsy specimens. ACMG/AMP Criteria applied: PM2, PP3, PM5, PS3, PM3 (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV000291465	SCV001247168	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463735	SCV004213748	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-07-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000274198	SCV000792416	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-06-23	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000291465	SCV001930638	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000291465	SCV001951564	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000274198	SCV002085507	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-07-07	no assertion criteria provided	clinical testing