ClinVar

Description

A Heterozygous Missense variant c.1621C>T in Exon 13 of the CAPN3 gene that results in the amino acid substitution p.Arg541Trp was identified. The observed variant has a minor allele frequency of 0.00004% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting a greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Conflicting interpretations of pathogenicityPathogenic(5); Likely pathogenic(1); Uncertain significance(1) with a status of (1 star) criteria provided, conflicting interpretations (Variation ID 498267 as of 2022-11-05). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 541 of the CAPN3 protein (p.Arg541Trp) (Milic A et al., 2005). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.