ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1030-1G>A

dbSNP: rs1555421263
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672816 SCV000797960 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-02-23 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000672816 SCV001164547 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-12-03 criteria provided, single submitter research The heterozygous c.1030-1G>A variant in CAPN3 was identified by our study in the compound heterozygous state with a pathogenic variant in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with LGMD and increases the likelihood that the p.Thr184ArgfsTer36 variant is pathogenic. The c.1030-1G>A variant in CAPN3 was reported in at least 1 individual in the literature (PMID: 18854869, 20635405), and was absent from large population studies. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to a frameshift and an abnormal or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. RNA and protein analyses of a muscle biopsy from an individual compound heterozygous with this variant and a pathogenic variant provide some evidence that the c.1030-1G>A variant may impact splicing and eliminate translation (PMID: 20635405). This variant has also been reported likely pathogenic in ClinVar (Variation ID: 556764). In summary, although additional studies are required to fully establish its clinical significance, the c.1030-1G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PVS1_moderate, PM3_Supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp RCV000672816 SCV003443456 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-01-02 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the CAPN3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 18854869). ClinVar contains an entry for this variant (Variation ID: 556764). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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