Submissions for variant NM_000070.3(CAPN3):c.1115+2T>C

dbSNP: rs1057524468

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436181	SCV000535649	pathogenic	not provided	2017-01-04	criteria provided, single submitter	clinical testing	The c.1115+2 T>C pathogenic variant in the CAPN3 gene destroys the canonical splice donor site in intron 8. It 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. The c.1115+2 T>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the c.1115+2 T>C variant has not been published to our knowledge, other splice site variants in the CAPN3 gene have been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2014).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003631123	SCV004446609	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-03-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 392385). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003631123	SCV005398196	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive limb-girdle muscular dystrophy 1 (MIM#253600). Dominant-negative is the suggested mechanism for autosomal dominant limb-girdle muscular dystrophy 4 (MIM#618129; PMIDs: 27259757, 28881388). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant limb-girdle muscular dystrophy is associated with milder presentation and later onset (PMID: 32342993). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other splice site variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least three other variants inthis splice region, c.1115+1G>A, c.1115+2T>A and c.1115+5G>C, have been reported in affected individuals (Clinvar, PMID: 32646536). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. It has been classified as pathogenic by a diagnostic laboratory in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003476018	SCV004211551	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-10-03	flagged submission	clinical testing