ClinVar Miner

Submissions for variant NM_000238.3(KCNH2):c.2371C>T (p.Arg791Trp) (rs138498207)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618893 SCV000738111 uncertain significance Cardiovascular phenotype 2017-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Biesecker Lab/Human Development Section,National Institutes of Health RCV000148535 SCV000055275 likely benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148535 SCV000190248 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058113 SCV000089633 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.
GeneDx RCV000586962 SCV000234155 uncertain significance not provided 2018-05-04 criteria provided, single submitter clinical testing The R791W variant of uncertain significance in the KCNH2 gene has been reported in one individual with LQTS, and was absent from more than 2,600 control alleles (Kapplinger et al., 2009). However, the ExAc database reports R791W was observed in 11/10340 (0.11% ) alleles from individuals of African ancestry, suggesting it may be a rare benign variant in this population. Nevertheless, the R791W 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. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Lastly, Anderson et al. (2014) expressed the R791W variant in the absence of a wildtype allele and observed normal protein trafficking to the cell membrane, but altered channel gating. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000586962 SCV000696024 uncertain significance not provided 2017-02-13 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.2371C>T (p.Arg791Trp) variant involves the alteration of a non-conserved nucleotide. 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 13/120900 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001064 (11/10340). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic KCNH2 variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been reported in a patient with suspected LQTS without strong evidence for causality. Functional study showed this variant with competent trafficking and moderate alteration on gating (Anderson_2014) with nearly normal values for the repolarizing outward potassium current density or Ikv11.1. Furthermore a LOF mechanism due to a reduction in Ikv11.1 is considered to be the predominant molecular mechanism of disease attributed to mutations in KCNH2. Therefore, the in-vivo relationship of this variant which results in normal traffcking and Ikv11.1 current density while modulating the gating properties of the voltage gated potassium channel is not clearly established. In addition, multiple clinical diagnostic laboratories classified this variant as VUS and one classified it as likely benign, all without evidence for independent evaluation. Taken together, this variant is classified as VUS-possibly benign until more information becomes available.
Invitae RCV000148535 SCV000752905 likely benign Long QT syndrome 2017-11-06 criteria provided, single submitter clinical testing

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