ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.145C>T (p.Arg49Cys) (rs794726871)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000710093 SCV000224136 pathogenic not provided 2016-05-12 criteria provided, single submitter clinical testing
Athena Diagnostics Inc 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 Institute Rare Disease Group, Broad Institute RCV000173055 SCV001164485 likely pathogenic 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,; 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).
Invitae RCV000173055 SCV001230940 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 49 of the CAPN3 protein (p.Arg49Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous or compound heterozygous state in several individuals affected with limb-girdle muscular dystrophy 2A (PMID: 18055493, 18334579, 19285864, 19556129). This variant has also been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with LGMD (PMID: 28403181). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 193037). 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000710093 SCV001246422 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Counsyl RCV000173055 SCV000790306 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2017-03-10 no assertion criteria provided clinical testing

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