Submissions for variant NM_000070.3(CAPN3):c.145C>T (p.Arg49Cys)

gnomAD frequency: 0.00001  dbSNP: rs794726871

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710093	SCV000224136	pathogenic	not provided	2016-05-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710093	SCV000255652	likely pathogenic	not provided	2018-08-27	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in three or more cases with a recessive pathogenic variant in the same gene.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000173055	SCV001164485	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Arg49Cys variant in CAPN3 was identified by our study in the compound heterozygous state, with reported VUS variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.002437% (6/246158) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794726871). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg49Cys variant in CAPN3 has been reported in 2 individuals with LGMD (PMID: 18334579, 19285864). Also, the presence of this variant in combination with a reported pathogenic variant and in an individual with LGMD increases the likelihood that the p.Arg49Cys variant is pathogenic (Variation ID: 166790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This missense variant affects the same residue as the likely pathogenic p.Arg49His variant, raising the possibility that a change at this residue may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg49Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PM5, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000173055	SCV001230940	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-12-06	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 49 of the CAPN3 protein (p.Arg49Cys). This variant is present in population databases (rs794726871, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18055493, 18334579, 19285864, 19556129, 28403181). 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: 193037). 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 95%. 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: 16650086, 17318636, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000710093	SCV001246422	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000710093	SCV002025053	likely pathogenic	not provided	2019-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114322	SCV003801333	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.145C>T (p.Arg49Cys) results in a non-conservative amino acid change in 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 2.4e-05 in 251372 control chromosomes. c.145C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Groen_2007, Charlton_2009, Meinke_2020, Alharbi_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003462272	SCV004213741	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000173055	SCV000790306	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-03-10	no assertion criteria provided	clinical testing