Submissions for variant NM_000238.4(KCNH2):c.2860C>T (p.Arg954Cys)

gnomAD frequency: 0.00004  dbSNP: rs141401803

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181898	SCV000234201	uncertain significance	not provided	2022-03-31	criteria provided, single submitter	clinical testing	Observed in individuals with sudden infant death syndrome (SIDS) or sudden unexpected death (SUD) (Arnestad et al., 2007; Sanchez et al., 2016); Also reported in an individual with an increased QTc interval during macrolide treatment that normalized after drug withdrawal, as well as in her daughter who had a QTc of approximately 450ms (Biliczki et al., 2008); Published functional studies demonstrate a damaging effect as this variant results in reduced channel current and significant alterations in channel biophysical properties (Rhodes et al., 2008; Biliczki et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21778721, 23304551, 24223155, 21215473, 28316956, 26633542, 27026747, 18675227, 27930701, 34502138, 22581653, 32048431, 32268277, 17210839, 31043699, 18222468)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588938	SCV000696028	likely pathogenic	Cardiovascular phenotype	2016-05-23	criteria provided, single submitter	clinical testing	Variant summary: The KCNH2 c.2860C>T (p.Arg954Cys) variant involves the alteration of a non-conserved nucleotide with 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large, broad control population, ExAC with an allele frequency of 3/36306 (1/12102, frequency: 0.00008263), which does not exceed the estimated maximal expected allele frequency for a pathogenic KCNH2 variant of 1/10000 (0.0001). In addition, the ExAC cohort does contain individuals that could harbor a KCNH2 phenotype. The variant of interest has been reported in multiple affected individuals via publications including 1 SIDS case and a 59 y/o mother, who had an abnormally prolonged QT interval during macrolide antibiotic treatment that normalized fully after drug withdrawal (QTc lead II: 420 ms). Her history was unremarkable for palpitations, unexplained syncope, or cardiac arrest. Her daughter (age 41 years, QTc ~450 ms) carried the mutation and did not have a history of palpitations or syncope. Functional studies do suggest the variant to inhibit biophyisical properties. In addition, multiple clinical laboratories cite the variant as "pathogenic," although information for an independent evaluation is not provided. Therefore, due to the limited available clinical information, the variant of interest is classified as likely pathogenic until additional information becomes available.
Ambry Genetics	RCV000588938	SCV000737773	uncertain significance	Cardiovascular phenotype	2019-06-04	criteria provided, single submitter	clinical testing	The p.R954C variant (also known as c.2860C>T), located in coding exon 12 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2860. The arginine at codon 954 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in a sudden infant death syndrome and sudden death cohorts (Arnestad M et al. Circulation, 2007 Jan;115:361-7; Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358). It is also reported in an asymptomatic patient with macrolide-induced QT prolongation that normalized fully after drug withdrawal, as well as in the asymptomatic child who had a QTc of approximately 450ms (Biliczki P et al. Heart Rhythm. 2008;5:1159-67). Using transient transfection of CHO cells, this alteration was reported to result in reduced ionic current (Biliczki P et al. Heart Rhythm. 2008;5:1159-67; Rhodes TE et al. J Mol Cell Cardiol. 2008;44:571-81). 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.
Invitae	RCV000685653	SCV000813141	uncertain significance	Long QT syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 954 of the KCNH2 protein (p.Arg954Cys). This variant is present in population databases (rs141401803, gnomAD 0.005%). This missense change has been observed in individuals with KCNH2-related conditions and/or Long QT (PMID: 17210839, 18675227, 27930701; Invitae). ClinVar contains an entry for this variant (Variation ID: 67444). 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: 17210839, 18222468, 18675227). This variant disrupts the p.Arg954 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 27026747), which suggests that this may be a clinically significant amino acid residue. 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.
Color Diagnostics, LLC DBA Color Health	RCV001841728	SCV001342756	uncertain significance	Cardiac arrhythmia	2023-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 954 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown this variant may reduce ionic current and accelerate channel deactivation (PMID: 17210839, 18222468, 18675227). This variant has been reported in individuals affected with sudden infant death syndrome (PMID: 17210839), drug-induced QT prolongation (PMID: 18675227), and atrial fibrillation (Han et al., 2010). This variant has also been identified in 8/217960 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058171	SCV000089691	not provided	SUDDEN INFANT DEATH SYNDROME		no assertion provided	literature only	This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:17210839;PMID:18675227). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.