Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005000366 | SCV005620246 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy | 2025-01-09 | reviewed by expert panel | curation | The NM_000070.3: c.1027G>T (p.Glu343Ter) variant in CAPN3, which is also known as p.(Glu343del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least five individuals with features of limb girdle muscular dystrophy (PMID: 34628793, 30564623; LOVD CAPN3_000602; ClinVar SCV000953543.3 internal data communication), including in unknown phase with a pathogenic variant in two cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 30564623; LOVD Individual #00222348; ClinVar SCV000953543.3 internal data communication) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy (PP4). The highest population minor allele frequency of the variant is 0.00005787 (2/34560 exome chromosomes) in the Admixed American population of gnomAD v2.1.1, which is less than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1, PM3, PP4, PM2_Supporting. |
| Eurofins Ntd Llc |
RCV000627356 | SCV000701518 | pathogenic | not provided | 2018-04-12 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000627356 | SCV000748349 | pathogenic | not provided | 2018-04-24 | criteria provided, single submitter | clinical testing | The E343X variant in the CAPN3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The E343X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret E343X as a pathogenic variant. |
| Labcorp Genetics |
RCV000591954 | SCV000830883 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2024-04-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu343*) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is present in population databases (rs766334893, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 497182). For these reasons, this variant has been classified as Pathogenic. |
| Medical Molecular Genetics Department, |
RCV000591954 | SCV005397143 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2024-08-11 | criteria provided, single submitter | clinical testing | By applying ACMG guidelines: According to insilico studies, the variant is classified as deleterious (PP3),our study patient’s clinical phenotype is typically correlated to the disease (PP4), it showed an extremely low frequency in gnomAD population databases (PS4). Null variant in a gene where loss of function is a known mechanism of disease (PVS1). so according to ACMG guidlines it is classified as variant of uncertain significance. |
| Baylor Genetics | RCV003459462 | SCV004213754 | likely pathogenic | Muscular dystrophy, limb-girdle, autosomal dominant 4 | 2023-07-10 | flagged submission | clinical testing |