Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Agnes Ginges Centre for Molecular Cardiology, |
RCV000584803 | SCV000692514 | likely pathogenic | Long QT syndrome 1 | 2017-03-16 | criteria provided, single submitter | research | The KCNH2 Tyr427Cys variant is located in the Transmembrane/ S1 domain. It has been reported in 2 long QT probands and was absent from 1300 controls (Itoh H, et al., 2016; Kapplinger, et al., 2009). The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in one long QT proband with no family history of disease or SCD. Interestingly, different rare variants at this position (Tyr427Ser and Tyr427His) have also been reported in long QT individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. The variant was discussed at our multidisciplinary pathogenicity meeting and it was agreed based on the above evidence that it should be considered as "likely pathogenic". |
| Labcorp Genetics |
RCV005089474 | SCV005835336 | uncertain significance | Long QT syndrome | 2024-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 427 of the KCNH2 protein (p.Tyr427Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome or clinical features of this condition (PMID: 19716085, 27920829, 36861347). ClinVar contains an entry for this variant (Variation ID: 67179). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV005403747 | SCV006070080 | pathogenic | Cardiovascular phenotype | 2023-09-20 | criteria provided, single submitter | clinical testing | |
| Cardiovascular Biomedical Research Unit, |
RCV000057886 | SCV000089406 | not provided | Congenital long QT syndrome | no assertion provided | literature only | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. |