Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000182192 | SCV000234495 | uncertain significance | not provided | 2014-04-23 | criteria provided, single submitter | clinical testing | p.Asp488Glu (GAC>GAA): c.1464 C>A in exon 11 of the KCNQ1 gene (NM_000218.2). A variant of unknown significance has been identified in the KCNQ1 gene. The D488E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D488E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D488E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues have not been reported in association with arrhythmia, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s). |
Labcorp Genetics |
RCV000701786 | SCV000830604 | uncertain significance | Long QT syndrome | 2021-08-30 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with glutamic acid at codon 488 of the KCNQ1 protein (p.Asp488Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs778041701, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with KCNQ1-related conditions. ClinVar contains an entry for this variant (Variation ID: 200849). 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. |
Color Diagnostics, |
RCV001842873 | SCV001352009 | uncertain significance | Cardiac arrhythmia | 2019-10-09 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 488 of the KCNQ1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002390457 | SCV002697198 | uncertain significance | Cardiovascular phenotype | 2018-12-20 | criteria provided, single submitter | clinical testing | The p.D488E variant (also known as c.1464C>A), located in coding exon 11 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 1464. The aspartic acid at codon 488 is replaced by glutamic acid, an amino acid with highly similar properties, and is located in the C-terminal, cytoplasmic region of the protein. This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other 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. |
All of Us Research Program, |
RCV000701786 | SCV004836446 | uncertain significance | Long QT syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 488 of the KCNQ1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |