CAPN3 p.Ala133Val

The NM_000070.3: c.398C>T variant in CAPN3 is a missense variant predicted to cause substitution of alanine by valine at position 133, p.(Ala133Val). This variant has been reported in two unrelated individuals with a clinical diagnosis of LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (c.598_612del p.(Phe200_Leu204del), 1.0 pt x2, PMID: 16141003, LOVD individuals #00214184, #00214185; PM3_Strong, PP4). However, it has also been observed in a homozygous state or in trans with a second presumed diagnostic CAPN3 variant (c.133G>A p.(Ala45Thr), c.1303G>A (p.Glu435Lys)) in three individuals without a clear LGMD phenotype (ClinVar SCV001985435.3, SCV003509679.1 internal data communication). The filtering allele frequency of this variant is 0.0001855 (the upper threshold of the 95% CI of 16/86246 exome chromosomes) in the South Asian population in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Of note, the South Asian population also includes one homozygous individual of unknown age. The computational predictor REVEL gives a score of 0.959, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, while 6 Bayesian points were awarded to this variant based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (PM3_Strong, PP3, PP4), given the conflicting evidence, the VCEP has opted to classify it as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy (LGMD VCEP specifications version 1.0.0; 03/25/2025).