Submissions for variant NM_000238.4(KCNH2):c.3107G>A (p.Gly1036Asp)

gnomAD frequency: 0.00013  dbSNP: rs199473022

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454975	SCV000539430	uncertain significance	not specified	2016-03-31	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 2 probands (Tester 2005 and Itoh 2015); ExAC: 1/3460 European; ClinVar: 1 Path; Immunoblot analysis (nZ2) of transiently transfected HEK293 cells revealed the the mutation trafficked similar to WT (Fig. 6b; Andersen 2014).
Color Diagnostics, LLC DBA Color Health	RCV001841742	SCV000904466	uncertain significance	Cardiac arrhythmia	2023-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 1036 of the KCNH2 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies have shown that the variant affects deactivation and inactivation current of the channel in vitro (PMID: 18675227). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 15840476, 18675227, 26066609, 26669661, 29622001). This variant has been identified in 16/176308 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.
Invitae	RCV000795860	SCV000935338	uncertain significance	Long QT syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1036 of the KCNH2 protein (p.Gly1036Asp). This variant is present in population databases (rs199473022, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 15840476, 18675227, 19804510, 23174487, 26066609, 26669661, 29622001). ClinVar contains an entry for this variant (Variation ID: 67469). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18675227). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454975	SCV001339153	uncertain significance	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.3107G>A (p.Gly1036Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 176308 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), suggesting that the variant might be a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the variant, c.3107G>A, has also been reported in the literature in individuals affected with Long QT Sydrome (LQTS; examples: Tester_2005, Biliczki_2008, Giudicessi_2012, Mullally_2013, Steffensen_2015, Itoh_2016, Koponen_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated moderately altered channel function in vitro (Biliczki_2013). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001548137	SCV001767994	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Reported in patients with LQTS or referred for LQTS genetic testing (Tester et al., 2005; Biliczki et al., 2008; Kapa et al., 2009; Schmitt et al., 2009; Giudicesi et al., 2012; Steffensen et al., 2015); at least one patient with LQTS harbored additional cardiogenetic variants (Steffensen et al., 2015); In vitro functional analysis using Chinese hamster ovary cells demonstrated decreased potassium channel current in the presence of G1036D (Biliczki et al., 2009), though it is not clear how well these studies reproduce in vivo conditions; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 19804510, 22581653, 26147798, 15840476, 25417810, 26066609, 19841300, 22949429, 18675227, 31618753, 23174487, 26669661, 29622001)
Fulgent Genetics, Fulgent Genetics	RCV002477190	SCV002788129	uncertain significance	Short QT syndrome type 1; Long QT syndrome 2	2022-04-22	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058197	SCV000089717	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:15840476;PMID:18675227;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.