ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1810G>A (p.Gly604Ser) (rs199473522)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181821 SCV000234124 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing The Gly604Ser mutation in the KCNH2 gene has been published multiple times in association with LQTS, and has not been detected in over 400 control chromosomes in various studies (Jongbloed R et al., 1999; Splawski I et al., 2000; Van Langen I et al., 2003; Lupoglazoff J et al., 2004; Zhang Y et al., 2007; Huo J et al., 2008). Lupoglazoff et al. reported Gly604Ser in a neonate with LQTS, heart failure, and sudden death. Similarly, Zhang et al. reported the Gly604Ser mutation in a large Chinese family with LQTS and history of sudden death. The same group also reported functional studies demonstrating that Gly604Ser, located in the S5-pore domain, causes loss of function of the potassium channel by impairing the intracellular trafficking of the mutant as well as wild type HERG proteins to the cell membrane in a dominant-negative manner (Huo J et al., 2008). Furthermore, the NHLBI ESP Exome Variant Server reports Gly604Ser was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.
Invitae RCV000205578 SCV000259591 pathogenic Long QT syndrome 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 604 of the KCNH2 protein (p.Gly604Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with long QT syndrome (LQT) (PMID: 10220144, 10973849, 11854117, 12566525, 14998624, 17171344, 18441445, 19843919, 22402334, 22821100, 22949429, 23158531) and to segregate with disease in a large multigenerational family (PMID: 17171344). ClinVar contains an entry for this variant (Variation ID: 67281). Experimental studies using transfected mammalian cells have shown that this missense change has a dominant negative effect on KCNH2 trafficking to the cell membrane (PMID: 18386051, 25417810). For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057997 SCV000089517 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:10220144;PMID:10973849;PMID:11854117;PMID:12566525;PMID:14998624;PMID:15840476;PMID:17171344;PMID:18386051;PMID:18441445;PMID:19716085;PMID:19841300;PMID:22402334). 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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