Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000505746 | SCV000223329 | uncertain significance | not provided | 2018-02-02 | criteria provided, single submitter | clinical testing | The E485K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has been observed in one other individual referred for LQTS genetic testing at GeneDx; no informative segregation data is available. The E485K variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the E485K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. |
Invitae | RCV001325303 | SCV001516289 | uncertain significance | Long QT syndrome | 2022-05-05 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 190637). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 485 of the CACNA1C protein (p.Glu485Lys). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. |
Ambry Genetics | RCV002390404 | SCV002701894 | uncertain significance | Cardiovascular phenotype | 2021-06-28 | criteria provided, single submitter | clinical testing | The p.E485K variant (also known as c.1453G>A), located in coding exon 10 of the CACNA1C gene, results from a G to A substitution at nucleotide position 1453. The glutamic acid at codon 485 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |