Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000587153 | SCV000696036 | uncertain significance | not provided | 2016-12-19 | criteria provided, single submitter | clinical testing | Variant summary: The KCNH2 c.773C>T (p.Pro258Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was not found in 2166 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. An internal sample also carried a pathogenic variant in KCNQ1 c.502G>A/p.Gly168Arg. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. |
| Labcorp Genetics |
RCV001853975 | SCV002188064 | uncertain significance | Long QT syndrome | 2021-10-20 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with leucine at codon 258 of the KCNH2 protein (p.Pro258Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNH2-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 | RCV002404592 | SCV002672139 | uncertain significance | Cardiovascular phenotype | 2023-04-25 | criteria provided, single submitter | clinical testing | The p.P258L variant (also known as c.773C>T), located in coding exon 4 of the KCNH2 gene, results from a C to T substitution at nucleotide position 773. The proline at codon 258 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002491163 | SCV002783941 | uncertain significance | Short QT syndrome type 1; Long QT syndrome 2 | 2021-08-12 | criteria provided, single submitter | clinical testing |