ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate altered enzymatic activity (Velez et al., 2018) and the mutant mouse model exhibits a phenotype similar to that seen in humans (Wang et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32707200, 30986125, 31403230, 29472286, 29610848, 29245980)

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN5 function (PMID: 29472286). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN5 protein function. ClinVar contains an entry for this variant (Variation ID: 279987). This missense change has been observed in individual(s) with autosomal dominant neovascular inflammatory vitreoretinopathy (PMID: 29472286, 30986125). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 289 of the CAPN5 protein (p.Arg289Trp).

The alteration results in an amino acid change:_x000D_ _x000D_ The c.865C>T (p.R289W) alteration is located in exon 6 (coding exon 5) of the CAPN5 gene. This alteration results from a C to T substitution at nucleotide position 865, causing the arginine (R) at amino acid position 289 to be replaced by a tryptophan (W). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the CAPN5 c.865C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in a large Chinese family with 9 individuals in 4 generations affected with vitreoretinopathy, cataracts and retinitis pigmentosa starting in childhood, and it segregated with all affected individuals in that family (Wang, 2018). In addition, it has been reported de novo in two unrelated patients with vitreoretinopathy, hearing loss, and additional findings (O'Keefe, 2019; Velez, 2018). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R289 amino acid is conserved in available vertebrate species through reptiles. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ A mouse model harboring this alteration was found to have an abnormally proliferative retinal pigment epithelium (RPE) layer (Wang, 2018) and in vitro studies have demostrated a gain-of-function effect with hyperactivation of the calpain protease even in the absence of calcium levels typically required for activation of wild type CAPN5 (Velez, 2018). The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.R289W alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The CAPN5 c.865C>T variant is predicted to result in the amino acid substitution p.Arg289Trp. This variant has been reported as de novo in four pediatric patients with vitreoretinopathy phenotypes (Velez et al. 2018. PubMed ID: 29472286; O'Keefe et al. 2019. PubMed ID: 30986125; Xia et al. 2022. PubMed ID: 36369866). This variant was also reported in a patient from a posterior segment uveitis cohort (Li et al. 2020. PubMed ID: 32707200). A functional analysis showed that this variant had a gain of function effect, leading to increased the proteolytic activity of CAPN5 (Velez et al. 2018. PubMed ID: 29472286). This variant has not been reported in a large population database, indicating this variant is rare and has been interpreted as pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/279987/). This variant is interpreted as pathogenic.