Integration of validated functional evidence to support the pathogenicity of KCNH2 variants

Aljassar, Reema W. and Shen, Qianyi and Albash, Buthaina and Vandenberg, Jamie I. and Ebrahim, Mohammad A. and Ng, Chai-Ann (2024) Integration of validated functional evidence to support the pathogenicity of KCNH2 variants. Genetics in Medicine Open, 2. p. 101868. ISSN 29497744

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Link to published document: https://doi.org/10.1016/j.gimo.2024.101868

Abstract

Functional investigation of genetic variants found in long QT syndrome can provide evidence that is needed to confirm the genetic diagnosis and establish the cause of the condition. We performed functional assessment to determine the z-score, using a clinically calibrated automated patch clamp assay, for 2 missense KCNH2 variants found in 2 families that have been diagnosed with long QT syndrome. These variants are currently classified as variant of uncertain significance in ClinVar. The z-scores for homozygous and heterozygous NM_000238.4:c.1819A>T p.(Ile607Phe) from family 1 were -5.16 and -3.97, respectively, and for heterozygous NM_000238.4:c.1832A>G p.(Tyr611Cys) from family 2 was -6.63. The z-scores for these variants are consistent with severe loss-of-function phenotypes. We have established the genetic cause of the long QT syndrome in these 2 families by providing validated functional evidence that supports the pathogenicity of p.(Ile607Phe) and p.(Tyr611Cys). Clinical diagnosis of long QT syndrome has been very successful in providing adequate clinical management for patients. However, functional assessment of variants found in these patients by using variant-specific z-scores can further enhance the current clinical management of patients with long QT syndrome through shared decision making based on validated experimental evidence.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 02 May 2025 04:29
Last Modified: 02 May 2025 04:29
URI: https://eprints.victorchang.edu.au/id/eprint/1628

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