ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.209A>G (p.His70Arg) (rs199473419)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181934 SCV000234237 pathogenic not provided 2018-11-05 criteria provided, single submitter clinical testing The H70R pathogenic variant has been previously reported in several individuals in association with LQTS (Splawski et al., 2000; Moss et al., 2002; Tester et al., 2005; Kapa et al., 2009; Kapplinger et al., 2009; Medlock et al., 2012; Vijayakumar et al., 2014). Furthermore, H70R is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).Although H70R is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs within the aminoterminal cytoplasmic PAS (PER-ARNT-SIM) domain, at a position that is conserved in mammals. Furthermore, functional studies of the KCNH2 channel in Xenopus oocytes showed that H70R causes an accelerated rate of current deactivation, compared to the wild-type channel (Chen et al., 1999). Additionally, using a high-throughput zebrafish cardiac assay, H70R showed reduced cardiac repolarization compared to the wild-type channel (Jou et al., 2013). Moreover, in vitro studies have demonstrated H70R has a severe effect on protein folding stability compared to wild-type channel which may impact function (Harley et al., 2012). Finally, a pathogenic missense variant at the same residue (H70N) has been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this residue.
Invitae RCV000460303 SCV000543479 likely pathogenic Long QT syndrome 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 70 of the KCNH2 protein (p.His70Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome  (PMID: 22949429, 10973849, 11854117, 25294783, Invitae) ClinVar contains an entry for this variant (Variation ID: 67363). This variant identified in the KCNH2 gene is located in the cytoplasmic PAS region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit Experimental studies have shown that while this missense change  does not affect the trafficking of the channel to the cell membrane (PMID: 22396785, 21536673), it affects the function of the KCNH2 channel (PMID: 10187793, 23303164). However, there is also conflicting data from one study, suggesting that there is no effect on channel function (PMID: 21536673). In summary this rare missense variant has been reported in several affected individuals and has been shown to affect aspects of protein function. For these reasons it has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000181934 SCV001714256 likely pathogenic not provided 2021-01-26 criteria provided, single submitter clinical testing PS3, PS4_Moderate, PM1, PM2_Supportingm PP3
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058083 SCV000089603 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:10187793;PMID:10973849;PMID:11854117;PMID:15051636;PMID:15840476;PMID:19716085;PMID:19841300;PMID:21536673;PMID:22396785). 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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