ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1840C>T (p.Arg614Cys) (rs141401803)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181898 SCV000234201 likely pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing The R954C likely pathogenic variant in the KCNH2 gene has been reported association sudden infant death syndrome (SIDS) (Arnestad et al., 2007; Sanchez et al., 2016). This variant has also been 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). Functional studies indicated R954C results in reduced current density and partial loss of function of the KCNH2 channel (Rhodes et al., 2008). This study notes that the functional impairments were mild, hence suggesting additional genetic or environmental factors may be needed to result in arrhythmia. Additional functional studies by Biliczki et al. (2008) also demonstrated that mutant R954C ionic currents were reduced compared to wild type, and that R954C exhibited significant alterations in biophysical properties. The R954C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R954C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is conserved only through mammals and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Integrated Genetics/Laboratory Corporation of America 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 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000685653 SCV000813141 uncertain significance Long QT syndrome 2018-05-14 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.
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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