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

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 18, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000057913.16

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_001406753.1:c.1186C>T
NM_001406755.1:c.1297C>T
NM_001406756.1:c.1186C>T
NM_001406757.1:c.1174C>T
NM_172056.3: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_001393682.1:p.His396Tyr
NP_001393684.1:p.His433Tyr
NP_001393685.1:p.His396Tyr
NP_001393686.1:p.His392Tyr
NP_742053.1:p.His492Tyr
NP_742053.1:p.His492Tyr
NP_742054.1:p.His152Tyr
NP_742054.1:p.His152Tyr
LRG_288t1:c.1474C>T
LRG_288t2:c.1474C>T
LRG_288t3:c.454C>T
LRG_288:g.30419C>T
LRG_288p1:p.His492Tyr
LRG_288p2:p.His492Tyr
LRG_288p3:p.His152Tyr
NC_000007.13:g.150649596G>A
NM_000238.3:c.1474C>T
NM_172056.2:c.1474C>T
NM_172057.2:c.454C>T
NR_176254.1:n.1882C>T
NR_176255.1:n.755C>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_001406753.1:c.1186C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1297C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1186C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1174C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1474C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Congenital long QT syndrome (RWS)
Synonyms:: Familial long QT syndrome; Romano-Ward syndrome; Ventricular fibrillation with prolonged QT interval
Identifiers:: MONDO: MONDO:0019171; MedGen: C1141890; Orphanet: 768; OMIM: PS192500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000089433	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 12808265, 19843919, 22581653
SCV000966928	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Mar 18, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29766885, 27816319, 19843919, 12808265, 24057343, 27041096, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000089433

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

no classification provided

not provided

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000966928

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Mar 18, 2020)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Paralogous annotation of disease-causing variants in long QT syndrome genes.

Ware JS, Walsh R, Cunningham F, Birney E, Cook SA.

Hum Mutat. 2012 Aug;33(8):1188-1191. doi: 10.1002/humu.22114. Epub 2012 Jun 7.

PubMed [citation]

PMID:: 22581653
PMCID:: PMC4640174

Impact of Updated Diagnostic Criteria for Long QT Syndrome on Clinical Detection of Diseased Patients: Results From a Study of Patients Carrying Gene Mutations.

Hayashi K, Konno T, Fujino N, Itoh H, Fujii Y, Imi-Hashida Y, Tada H, Tsuda T, Tanaka Y, Saito T, Ino H, Kawashiri MA, Ohta K, Horie M, Yamagishi M.

JACC Clin Electrophysiol. 2016 Jun;2(3):279-287. doi: 10.1016/j.jacep.2016.01.003. Epub 2016 Mar 23.

PubMed [citation]

PMID:: 29766885

See all PubMed Citations (8)

Details of each submission

From Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, SCV000089433.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966928.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

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 (http://gnomad.broadinstitute.org) 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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	1	not provided

Last Updated: Apr 20, 2024

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