Submissions for variant NM_000238.4(KCNH2):c.1426G>A (p.Val476Ile)

gnomAD frequency: 0.00001  dbSNP: rs199472908

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454941	SCV000539447	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in only 1 LQT proband
Invitae	RCV001303669	SCV001492920	uncertain significance	Long QT syndrome	2022-09-17	criteria provided, single submitter	clinical testing	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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 67200). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 19716085). This variant is present in population databases (rs199472908, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 476 of the KCNH2 protein (p.Val476Ile).
Color Diagnostics, LLC DBA Color Health	RCV001841699	SCV002053377	uncertain significance	Cardiac arrhythmia	2023-05-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 476 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not cause trafficking deficits in transfected HEK293 cells (PMID: 36339618). This variant has been reported in one individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 2/251476 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.
Fulgent Genetics, Fulgent Genetics	RCV002477187	SCV002776978	uncertain significance	Short QT syndrome type 1; Long QT syndrome 2	2021-08-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298109	SCV003997348	uncertain significance	Cardiovascular phenotype	2023-03-21	criteria provided, single submitter	clinical testing	The p.V476I variant (also known as c.1426G>A), located in coding exon 6 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1426. The valine at codon 476 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in a case from a long QT genetic testing cohort (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). One study suggested this variant may not significantly impact protein trafficking (Zhang Y et al. Front Pharmacol, 2022 Oct;13:1010119). This amino acid position is highly conserved in available 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057908	SCV000089428	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.