ClinVar

Description

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNE3 function (PMID: 19306396, 22987075). 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 alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 126426). This missense change has been observed in individual(s) with clinical features of long QT syndrome or Brugada syndrome. However, in two of these individuals additional variants were also identified in other genes associated with long QT syndrome, which suggests that this c.10A>G variant was not the primary cause of disease. (PMID: 19306396, 22987075, 28747690). This variant is present in population databases (rs200856070, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 4 of the KCNE3 protein (p.Thr4Ala).