ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1633C>T (p.Arg545Cys) (rs143512106)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148524 SCV000826893 uncertain significance Long QT syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 885 of the KCNH2 protein (p.Arg885Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs143512106, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with long QT syndrome (PMID: 18752142, 17210839, 19716085). ClinVar contains an entry for this variant (Variation ID: 67422). Experimental studies have shown that this missense change behaves biophysically similar to the wild-type in vitro (PMID: 18222468). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780364 SCV000917560 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.2653C>T (p.Arg885Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 275594 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), suggesting the variant may be benign. However, this observation must be interpreted cautiously due to the presence of potenially affected individuals in the ExAC and gnomAD databases. c.2653C>T has been reported in the literature in individuals affected with Arrhythmia without strong evidence for or against pathogenicity. However, one publication reported a co-occurrence with a pathogenic KCNH2 variant (c.1557+1G>C), providing supporting evidence for a benign role (Burns_2016). One publication reports experimental evidence suggesting there is no functional effect of the variant, though the data was not presented for review (Rhodes_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional information becomes available.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058147 SCV000089667 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:16244680;PMID:17210839;PMID:18752142;PMID:19716085;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148524 SCV000190236 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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