rs199472910

Positions:

chr7-150952508-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The ENST00000262186.10(KCNH2):c.1474C>T(p.His492Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H492L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

KCNH2
ENST00000262186.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1O:1

Conservation

PhyloP100: 9.80

Variant links:

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in ENST00000262186.10

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 7-150952508-G-A is Pathogenic according to our data. Variant chr7-150952508-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67204.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Pathogenic=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.1474C>T	p.His492Tyr	missense_variant	6/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.1474C>T	p.His492Tyr	missense_variant	6/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000403

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital long QT syndrome

Pathogenic:1Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2020	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 -

Short QT syndrome type 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000067204). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Long QT syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2019

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. -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His492 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 30369311), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect KCNH2 function (PMID: 19843919). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67204). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 12808265, 19843919, 24057343, 27816319). This variant is present in population databases (rs199472910, gnomAD 0.01%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 492 of the KCNH2 protein (p.His492Tyr). -

Short QT syndrome type 1;C3150943:Long QT syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 11, 2021

- -

KCNH2-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2023

The KCNH2 c.1474C>T variant is predicted to result in the amino acid substitution p.His492Tyr. This variant was reported in multiple individuals with long-QT syndrome (Case 4, Itoh. 2009. PubMed ID: 19843919; reported as HERG H492Y, Inoue. 2003. PubMed ID: 12808265; Bando et al 2013. PubMed ID: 24057343; see Table 2, Fujii. 2017. PubMed ID: 27816319). This variant was interpreted as a causative variant for long-QT syndrome (Table S7, Ware et al 2012. PubMed ID: 22581653). Functional studies suggest that variant may slightly alter KCNH2 normal function (Figure 5, Itoh. 2009. PubMed ID: 19843919). In ClinVar, this variant is interpreted as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/67204/?new_evidence=true). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-150649596-G-A). This variant is interpreted as likely pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 18, 2020

This missense variant replaces histidine with tyrosine at codon 492 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a mild decrease in current density and did not have a dominant negative effect (PMID: 19843919). This variant has been reported in over ten Japanese individuals affected with or suspected of having long QT syndrome (PMID: 12808265, 24057343, 27041096, 27816319, 29766885). Some of these individuals who also carried a pathogenic variant in the same or different gene showed a more severe phenotype (PMID: 24057343, 27816319). Multiple heterozygous individuals did not show a prolonged QT interval (PMID: 24057343, 27816319). This variant has been identified in 3/251464 chromosomes (3/18394 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). In summary, although additional studies are required to fully establish its clinical significance, the available evidence indicates that this variant is likely pathogenic for autosomal dominant long QT syndrome, although 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 pathogenic variants. Therefore, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The p.H492Y variant (also known as c.1474C>T), located in coding exon 6 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1474. The histidine at codon 492 is replaced by tyrosine, an amino acid with similar properties. This variant has been detected in a number of individuals of Japanese ancestry with long QT syndrome (LQTS), suspected LQTS, or acquired LQTS precipitated by an additional factor. However, individuals with this and a second variant in LQTS-associated genes had more severe phenotype, and some individuals with only the p.H492Y were apparently unaffected (Inoue M et al. Circ J, 2003 Jun;67:495-8; Nagaoka I et al. Circ J, 2008 May;72:694-9; Itoh H et al. Circ Arrhythm Electrophysiol, 2009 Oct;2:511-23; Yoshinaga M et al. Circ Arrhythm Electrophysiol, 2014 Feb;7:107-12; Bando S et al. Heart Vessels, 2014 Jul;29:554-9; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70; Jang SY et al. Pacing Clin Electrophysiol, 2017 Mar;40:232-241; Fujii Y et al. J Cardiol, 2017 Jul;70:74-79). In vitro functional studies have indicated that this variant resulted in protein expression and peak cannel current comparable to wild type (Itoh H et al. Circ Arrhythm Electrophysiol, 2009 Oct;2:511-23; Perry MD et al. J Physiol, 2016 Jul;594:4031-49). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.2

.;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.6

D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.98

MutPred

0.89

.;Loss of methylation at K495 (P = 0.0778);.;

MVP

0.99

MPC

2.3

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over