ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1474C>T (p.His492Tyr) (rs199472910)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778143 SCV000914274 likely pathogenic Long QT syndrome 2 2019-04-05 criteria provided, single submitter clinical testing The KCNH2 c.1474C>T (p.His492Tyr) missense variant has been reported in at least four studies in which it has been identified in a total of 18 individuals of Japanese descent with long QT syndrome, including six individuals (four unrelated) in a compound heterozygous state, seven individuals (five unrelated) in a heterozygous state, and five individuals (three unrelated) in a double heterozygous state with a second variant in a different gene (Itoh et al. 2009; Bando et al. 2014; Fujii et al. 2016; Izumi et al. 2016). The majority of the individuals with two variants were found to have a prolonged QTc interval and a more severe phenotype compared to individuals with the p.His492Tyr variant alone (Fujii et al. 2016; Izumi et al. 2016). Fujii et al. (2016) suggest that the p.His492Tyr variant in a heterozygous state may be associated with a milder form of long QT syndrome. They also suggest that these individuals have latent long QT syndrome and presence of additional factors, such as hypokalemia, drugs, or bradycardia, may result in symptoms, as was noted in four individuals who developed syncope or torsade de pointes when other factors were also present. The variant was also found in two unaffected heterozygous family members (Bando et al. 2014), but was absent from at least 1300 controls. The His492Tyr variant is reported at a frequency of 0.00012 in the East Asian population of the Genome Aggregation Database, but this is based on two alleles so the variant is presumed to be rare. Itoh et al. (2009) performed functional studies using Chinese hamster ovary cells and found that compared to wild type, presence of the p.His492Tyr variant resulted in a mild decrease in current density, and did not have a dominant negative effect. Based on the collective evidence, the p.His492Tyr variant is classified as likely pathogenic for long QT syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000057913 SCV000966928 likely pathogenic Congenital long QT syndrome 2020-03-18 criteria provided, single submitter clinical testing The p.His492Tyr variant in KCNH2 has been reported in the heterozygous state in at least 7 individuals with long QT syndrome (LQTS): 4 with congenital LQTS and 3 with drug induced LQTS (Inoue 2003, Itoh 2009, Hayashi 2016, Fujii 2017). The variant has also been reported in 7 individuals with a more severe phenotype who had a second variant in KCNH2 or another LQTS gene (Bando 2014, Fujii 2017). The p.His492Tyr variant segregated with disease in at least 5 affected relatives from 3 families; however the variant was also observed in unaffected family members (Itoh 2009, Bando 2014, Fujii 2017). In vitro functional studies suggest that the p.His492Tyr variant does not significantly impact protein function (Itoh 2009). This variant has been identified in 3/18394 East Asian chromosomes by gnomAD ( and has been reported in ClinVar (Variation ID: 67204). Computational prediction tools and conservation analysis suggest that the p.His492Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS, though it may show reduced penetrance and a milder clinical presentation when observed in isolation and a more severe phenotype when observed in combination with other LQTS variants. ACMG/AMP Criteria applied: PS4_Moderate, PM3, PP1, PP3
Color RCV001180292 SCV001345179 likely pathogenic Arrhythmia 2020-03-18 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057913 SCV000089433 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:12808265;PMID:19843919). 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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