ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2242C>T (p.Arg748Ter)

gnomAD frequency: 0.00002  dbSNP: rs768090444
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen RCV004999212 SCV005620243 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-09 reviewed by expert panel curation The NM_000070.3: c.2242C>T p.(Arg748Ter) variant in CAPN3, which is also known as p.(Arg748del), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 21/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. mRNA analysis demonstrated reduced expression of the transcript containing the variant, consistent with nonsense mediated decay (PMID: 17157502) (PVS1). This variant has been detected in at least six individuals reported to have autosomal recessive LGMD (PMID: 25214167, 12461690, 16971480, 17157502, 18055493; Washington University internal clinic data communication). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 16971480), and in at least two cases, the variant was identified in trans with a second CAPN3 variant not yet curated by the VCEP and considered VUS (0.5 pts, PMID: 12461690, 17157502) (PM3). At least one patient with this variant was clinically suspected to have limb girdle muscular dystrophy and displayed reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PP4_Moderate; PMID: 16971480). The filtering allele frequency of the variant is 0.000114 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 3/68008), which is more than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). 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_Moderate.
Eurofins Ntd Llc (ga) RCV000725244 SCV000335247 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000279441 SCV000645489 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2025-01-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg748*) 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 (rs768090444, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 12461690, 16971480, 17157502, 18055493). ClinVar contains an entry for this variant (Variation ID: 283259). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000279441 SCV001369821 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-03-24 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3,PP4.
Revvity Omics, Revvity RCV000725244 SCV002018067 pathogenic not provided 2019-12-16 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000725244 SCV002770920 pathogenic not provided 2022-08-01 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with LGMD, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Baylor Genetics RCV003475902 SCV004211567 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-03-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005008239 SCV005637814 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-06-10 criteria provided, single submitter clinical testing
Counsyl RCV000279441 SCV001132143 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2016-12-06 no assertion criteria provided clinical testing
Natera, Inc. RCV000279441 SCV001456372 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-09-16 no assertion criteria provided clinical testing

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