CAPN3 p.Arg541Gln

The NM_000070.3: c.1622G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine at amino acid position 541 with glutamine, p.(Arg541Gln). This variant has been identified in at least 18 individuals with features consistent with LGMD (PMID: 10330340, 1641109, 32994280, 30564623, 16141003, 30919934; LOVD CAPN3_000024; GRASP-LGMD Consortium internal data communication; ClinVar SCV001164515.1), including in a homozygous state without reported consanguinity in three unrelated patients (1.0 pt, PMID: 10330340, 30919934). It has also been reported in unconfirmed phase with a pathogenic variant in at least six patients (c.2120A>G p.(Asp707Gly), 0.5 pts, PMID: 32994280, LOVD Individual #00311302; c.1469G>A p.(Arg490Gln), 0.5 pts, PMID: 16141003, LOVD Individual #00214226; c.550del p.(Thr184ArgfsTer36) x4, 2.0 pts, PMID: 16141003, LOVD Individuals #00214228, #00214229, GRASP-LGMD Consortium internal data communication; ClinVar SCV001164515.1 internal data communication) (PM3_Very Strong). At least one patient with this variant and another presumed diagnostic CAPN3 variant exhibited progressive limb girdle muscle weakness (PMID: 1614100; PP4). The highest population variant allele frequency in gnomAD v4.1.0 is 0.00002196 (2/91082 South Asian chromosomes), which is lower than the VCEP threshold of 0.0001 (PM2_Supporting). The computational predictor REVEL gives a score of 0.908, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). A minigene assay showed altered splicing in a minority of transcripts but without a significant reduction in normally spliced transcript (PMID: 32668095; PVS1_RNA not met). The SpliceAI score is 0.02. In summary, this variant meets criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG criteria applied, as specified by the LGMD VCEP (specifications version 2.0.0, 02/18/2026): PM3_Very Strong, PP4, PM2_Supporting, PP3.