Submissions for variant NM_000070.3(CAPN3):c.2380+2T>G

dbSNP: rs761935462

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779157	SCV000915671	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-10-24	criteria provided, single submitter	clinical testing	The CAPN3 c.2380+2T>G variant is a canonical splice site (donor) variant and is therefore predicted to disrupt or distort the normal gene product. The c.2380+2T>G variant has been reported in two studies, in which it is found in a total of three individuals with calpainopathy, including in one in a homozygous state and in one in a compound heterozygous state with a second missense variant (Groen et al. 2007; Fadaee et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele so the variant is presumed to be rare. Due to the potential impact of splice donor variants and the evidence from the literature, the variant is classified as a likely pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000779157	SCV001164525	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The homozygous c.2380+2T>G variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.0008967% (1/111516) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761935462). 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 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. The c.2380+2T>G variant is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. The c.2380+2T>G variant in CAPN3 has been reported in the homozygous state in 1 Iranian individual and in the compound heterozygous state, with a variant reported pathogenic by multiple submitters in ClinVar (Variation ID: 92414), in 1 individual with LGMD (PMID: 27020652, 18055493). Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive LGMD. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1_Moderate, PM3 (Richards 2015).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814232	SCV001755391	likely pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV000779157	SCV003442819	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-07-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 632230). Disruption of this splice site has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 18055493, 30056071, 32140910). This variant is present in population databases (rs761935462, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 22 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).
Pars Genome Lab	RCV003229862	SCV003926619	uncertain significance	Muscular dystrophy, limb-girdle, autosomal dominant 4		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003229862	SCV004211578	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-08-22	criteria provided, single submitter	clinical testing