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Dryad

Patch-clamp dataset (SyncroPatch384PE) for control variants used in a calibrated functional patch clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome

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Apr 19, 2022 version files 39.17 GB

Abstract

Modern sequencing technologies have revolutionised our detection of gene variants. However, in most genes, including KCNH2, the majority of missense variants are currently classified as variants of uncertain significance (VUS). The aim of this study was to investigate the utility of an automated patch-clamp assay for aiding clinical variant classification in the KCNH2 gene. The assay was designed according to recommendations proposed by the ClinGen Sequence Variant Interpretation Working Group. Thirty-one variants (17 pathogenic/likely pathogenic, 14 benign/likely benign) were classified internally as variant controls. They were heterozygously expressed in Flp-In HEK293 cells for assessing the effects of variant on current density and channel gating in order to determine the sensitive and specificity of the assay. All 17 pathogenic variant controls had reduced current density and 13/14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying moderate or supporting evidence strength for VUS reclassification. Inclusion of KCNH2 functional assay evidence enabled us to reclassify 6 out of 44 VUS as likely pathogenic. The high-throughput patch clamp assay can provide moderate strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value of developing automated patch clamp assays for functional characterisation of ion channel gene variants.