ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.2860C>T (p.Arg954Cys) (rs141401803)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181898 SCV000234201 likely pathogenic not provided 2019-10-04 criteria provided, single submitter clinical testing Reported association sudden infant death syndrome (SIDS) (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); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 21778721, 23304551, 24223155, 21215473, 28316956, 26633542, 27026747, 18675227, 18222468, 17210839, 27930701, 22581653, 31043699, 32048431)
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 2019-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 954 of the KCNH2 protein (p.Arg954Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs141401803, ExAC 0.01%). This variant has been reported in an individual with a drug-induced prolonged QT interval and in an infant with sudden unexplained death (PMID: 18675227, 17210839). ClinVar contains an entry for this variant (Variation ID: 67444). Experimental studies have shown that this missense change alters potassium channels consistent with a loss-of-function effect (PMID: 17210839, 18675227, 18222468). The observation of one or more missense substitutions at this codon (p.Arg954His) in affected individuals suggests that this may be a clinically significant residue (PMID: 27026747). 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 Health, Inc RCV001178345 SCV001342756 uncertain significance Arrhythmia 2019-09-30 criteria provided, single submitter clinical testing
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.

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