rs771188512

Description

The p.V315I variant (also known as c.943G>A), located in coding exon 10 of the CASQ2 gene, results from a G to A substitution at nucleotide position 943. The valine at codon 315 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was detected in a whole exome sequencing cohort not selected for cardiovascular indication; however clinical details were limited (Landstrom AP et al. Circ Arrhythm Electrophysiol. 2017 Apr;10(4)). This amino acid position is poorly conserved in available vertebrate species, and isoleucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces valine with isoleucine at codon 315 of the CASQ2 protein (p.Val315Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs771188512, ExAC 0.007%). This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.