Submissions for variant NM_000070.3(CAPN3):c.1381C>T (p.Arg461Cys)

gnomAD frequency: 0.00001  dbSNP: rs1274808359

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727349	SCV000707794	pathogenic	not provided	2017-04-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000592929	SCV000790925	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-10-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000592929	SCV000924496	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-06-15	criteria provided, single submitter	research	The homozygous p.Arg461Cys variant was identified by our study in one individual with limb-girdle musculardDystrophy. This variant has been identified in the literature in four homozygous probands and one proband that was compound heterozygous for the p.Arg461Cys variant as well as the c.801+1G>A variant (Minami et al. 1999, PMID: 10567047; Chae et al. 2001, PMID: 11525884). This variant has been identified in <0.01% (1/17240) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). The Arginine (Arg) at position 461 is highly conserved in mammals and evolutionarily distant species, supporting that a change at this position may not be tolerated. Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is also located in a mutational hotspot in a gene that does not have many benign missense mutations. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.
Invitae	RCV000592929	SCV000936749	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-12-20	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 461 of the CAPN3 protein (p.Arg461Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10567047, 11525884, 18337726). 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: 501440). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235305	SCV003934067	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1381C>T (p.Arg461Cys) results in a non-conservative amino acid change located in the Peptidase C2, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251432 control chromosomes (gnomAD). c.1381C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Chae_2011 and Duno_2008). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11525884, 18337726). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003471960	SCV004211571	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-09-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000727349	SCV004238520	likely pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000592929	SCV002085510	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-03	no assertion criteria provided	clinical testing