ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1043del (p.Gly348fs)

dbSNP: rs781013226
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000725901 SCV000340379 pathogenic not provided 2016-03-17 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000274925 SCV001164532 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-12-03 criteria provided, single submitter research The heterozygous p.Gly348ValfsTer4 variant in CAPN3 was identified by our study in one individual in the compound heterozygous state, with a likely pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD) The presence of this variant in combination with a likely pathogenic variant and in an individual with LGMD increases the likelihood that the p.Gly348ValfsTer4 variant is pathogenic. This variant has been identified in 0.002838% (3/105690) of European (non-Finnish) chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781013226). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 348 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of another likely pathogenic variant in an individual with Limb-Girdle Muscular Dystrophy. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015).
Invitae RCV000274925 SCV001226841 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly348Valfs*4) 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 (rs781013226, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive limb girdle muscular dystrophy (PMID: 15733273, 25135358). ClinVar contains an entry for this variant (Variation ID: 286813). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000725901 SCV002018066 pathogenic not provided 2019-08-07 criteria provided, single submitter clinical testing
Counsyl RCV000274925 SCV000795891 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-11-30 no assertion criteria provided clinical testing

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