CAPN3 p.Val594=

The NM_000070.3: c.1782G>A variant in CAPN3 is a synonymous variant that is not expected to influence the protein amino acid sequence, p.(Val594=) but affects the last nucleotide of exon 14. SpliceAI gives a delta score of 0.68 for loss of the canonical splice donor site for exon 14 and 0.63 for loss of the canonical acceptor, suggesting it may affect splicing. RNAseq analysis on RNA from blood from a carrier of this variant has demonstrated that it causes near-complete missplicing, including skipping of exons 14 and 15 as well as of exons 14-16. Both of these exon skipping events are expected to introduce a frameshift and premature truncation with nonsense mediated decay expected (ClinVar SCV006324308.1 internal data communication; PVS1_RNA_Strong). In skeletal muscle, it may be associated with skipping of exon 14 only, which would also be expected to introduce a frameshift, premature truncation, and nonsense-mediated decay. This variant has been observed in a heterozygous state in at least two individuals with progressive limb girdle muscle weakness, including in unconfirmed phase with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 0.5 pts, GRASP-LGMD Consortium internal data communication) and confirmed in trans with a VUS (0.25 pts, ClinVar SCV006324308.1 internal data communication) (PM3_Supporting, PP4). The Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000001695 (2/1179864 European (non-Finnish) alleles), which is less than the VCEP threshold (0.0001), meeting the criterion for PM2_Supporting. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 04/01/2026): PVS1_Strong_RNA, PM3_Supporting, PP4, PM2_Supporting.