NM_000238.4(KCNH2):c.1474C>T (p.His492Tyr) AND Long QT syndrome 2

Clinical significance:Likely pathogenic (Last evaluated: Apr 5, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000778143.1

Allele description [Variation Report for NM_000238.4(KCNH2):c.1474C>T (p.His492Tyr)]

NM_000238.4(KCNH2):c.1474C>T (p.His492Tyr)

Gene:
KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q36.1
Genomic location:
Preferred name:
NM_000238.4(KCNH2):c.1474C>T (p.His492Tyr)
HGVS:
  • NC_000007.14:g.150952508G>A
  • NG_008916.1:g.30419C>T
  • NM_000238.4:c.1474C>TMANE SELECT
  • NM_001204798.2:c.454C>T
  • NM_172056.2:c.1474C>T
  • NM_172057.3:c.454C>T
  • NP_000229.1:p.His492Tyr
  • NP_000229.1:p.His492Tyr
  • NP_001191727.1:p.His152Tyr
  • NP_742053.1:p.His492Tyr
  • NP_742054.1:p.His152Tyr
  • LRG_288t1:c.1474C>T
  • LRG_288t2:c.1474C>T
  • LRG_288:g.30419C>T
  • LRG_288p1:p.His492Tyr
  • LRG_288p2:p.His492Tyr
  • NC_000007.13:g.150649596G>A
  • NM_000238.3:c.1474C>T
  • p.His492Tyr
Protein change:
H152Y
Links:
dbSNP: rs199472910
NCBI 1000 Genomes Browser:
rs199472910
Molecular consequence:
  • NM_000238.4:c.1474C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.2:c.1474C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome 2 (LQT2)
Synonyms:
LONG QT SYNDROME 2, ACQUIRED, REDUCED SUSCEPTIBILITY TO
Identifiers:
MONDO: MONDO:0013367; MedGen: C3150943; Orphanet: 101016; Orphanet: 768; OMIM: 613688

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000914274Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Apr 5, 2019)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote.

Fujii Y, Matsumoto Y, Hayashi K, Ding WG, Tomita Y, Fukumoto D, Wada Y, Ichikawa M, Sonoda K, Ozawa J, Makiyama T, Ohno S, Yamagishi M, Matsuura H, Horie M, Itoh H.

J Cardiol. 2017 Jul;70(1):74-79. doi: 10.1016/j.jjcc.2016.09.010. Epub 2016 Nov 3.

PubMed [citation]
PMID:
27816319

Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.

Itoh H, Sakaguchi T, Ding WG, Watanabe E, Watanabe I, Nishio Y, Makiyama T, Ohno S, Akao M, Higashi Y, Zenda N, Kubota T, Mori C, Okajima K, Haruna T, Miyamoto A, Kawamura M, Ishida K, Nagaoka I, Oka Y, Nakazawa Y, Yao T, et al.

Circ Arrhythm Electrophysiol. 2009 Oct;2(5):511-23. doi: 10.1161/CIRCEP.109.862649. Epub 2009 Aug 2.

PubMed [citation]
PMID:
19843919
See all PubMed Citations (4)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000914274.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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