ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1115+5G>C

dbSNP: rs886039597
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255970 SCV000322497 likely pathogenic not provided 2015-12-18 criteria provided, single submitter clinical testing The c.1115+5 G>C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1115+5 G>C variant damages or destroys the natural splice donor site of intron 8 and is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants have been reported in the CAPN3 gene in association with LGMD2A (Stenson et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp RCV000822784 SCV000963601 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-05-20 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the CAPN3 gene. It does not directly change the encoded amino acid sequence of the CAPN3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 32646536). ClinVar contains an entry for this variant (Variation ID: 265521). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8 and introduces a premature termination codon (PMID: 32646536). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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