This variant has been identified in at least 8 individuals with features consistent with LGMD (PMID: 30989743, 10484770, 30564623, 17994539; LOVD CAPN3_000018; ClinVar SCV000645479.8 internal data communication), including confirmed in trans with a likely pathogenic or pathogenic variant in one case with LGMD (c.1711del p.(Leu571SerfsTer23), 1.0 pt, PMID: 17994539, 26404900), one case with hyperCKemia (c.1469G>A p.(Arg490Gln), 1.0 pt, PMID: 18854869, 14578192), and one case with chronic proximal muscle weakness (c.1715G>A (p.Arg572Gln), 1.0 pt, ClinVar SCV000645479.8 internal data communication). It has also been reported in unknown phase with a pathogenic variant in at least two patients (c.2182C>T p.(Gln728Ter), 0.5 pts, PMID: 30919934; c.550del, p.(Thr184ArgfsTer36), 0.5 pts, PMID: 30919934) and in unknown phase with a likely pathogenic variant in one patient (c.2440-1G>A, 0.25 pts, PMID: 30564623, LOVD Individual #00222689) (PM3_Very Strong). Currently 4.25 pts c.1711del p.(Leu571SerfsTer23) can be independently classified as at least LP: PM2_Supporting, PVS1 Co-occurrence: c.1466G>A is in gnomAD 2.1.0 c.550del p.(Thr184ArgfsTer36): different haplotypes c.2182C>T p.(Gln728Ter): not in gnomAD v2, co-occurrence cannot be assessed. Independently P (PM2_Supporting, PVS1, PP1, PP4) c.1469G>A p.(Arg490Gln): different haplotypes c.319G>T (p.Glu107Ter) is not in gnomAD v2, co-occurrence cannot be assessed c.1715G>A (p.Arg572Gln): different haplotypes. Independently at least LP (PP1, PP4, PP3, PM2_Supporting, PM3) Note, Magri 2015, Milic 2008 and Richard 1999, all report the same Italian patient. Unscored: ClinVar submissions LOVD Individual #00220999 (Nallamilli 2018) heterozygous for for c.1466G>A (p.Arg489Gln) c.2051-3C>G (provisionally curated, looks like will stay at VUS) LOVD Individual #00214077 (Richard 1999) heterozygous for c.1466G>A (p.Arg489Gln) and c.946-1G>A (not curated, Splice AI 0.92) duplicate with Saenz (2005) Unscoreable cases: LOVD Individual #00221940 (Nallamilli 2018) homozygous for c.1466G>A (p.Arg489Gln) and c.319G>T (p.Glu107Ter), indicating they are in cis. Cannot check co-occurrence prediction because p.(Glu107Ter) not in v2 exomes. not scored. LOVD Individual #00221248 (Nallamilli 2018) heterozygous for c.1466G>A (p.Arg489Gln) and c.319G>T (p.Glu107Ter), phase not determined. Do not score - same variants shown to be in cis in another individual.

At least one individual with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression in skeletal muscle, which is specific for CAPN3-related LGMD (PMID: 17994539; PP4_Moderate).

The computational predictor REVEL gives a score of 0.881, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). SpliceAI: no splice effect. GENEie: no cryptic site, benign, ML score 0.0.

The Grpmax population frequency of this variant is 0.0003738 in gnomAD v4.1.0 (28/74900 African/African American chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001). Therefore, PM2_Supporting is not met.

c.1465C>T p.(Arg489Trp): P in ClinVar, on priority list to be curated

The NM_000070.3: c.1466G>A variant in CAPN3 is a missense variant expected to result in the substitution of arginine for glutamine at residue 489, p.(Arg489Gln). A mini-gene assay showed that this variant may result in exon 11 skipping in a very small minority of transcripts; however, significant expression of transcripts with the normal annotated splice pattern was maintained (PMID: 32668095; PVS1_RNA not met).