rs199473035

Positions:

chr7-150945388-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000238.4(KCNH2):c.3457C>T(p.His1153Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000729 in 1,590,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1153Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7O:2

Conservation

PhyloP100: 4.75

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_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 112 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.3457C>T	p.His1153Tyr	missense_variant	15/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.3457C>T	p.His1153Tyr	missense_variant	15/15	1	NM_000238.4	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.2437C>T	p.His813Tyr	missense_variant	11/11	1			Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.4290C>T		non_coding_transcript_exon_variant	13/13

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000483

AC:

AN:

207056

Hom.:

AF XY:

0.0000623

AC XY:

AN XY:

112290

show subpopulations

Gnomad AFR exome

AF:

0.0000845

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000380

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000779

AC:

112

AN:

1438114

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

713072

show subpopulations

Gnomad4 AFR exome

AF:

0.0000605

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000969

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000917

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000749

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:1Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Oct 18, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 10-10-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Research Institute, Imperial College London Diabetes Centre	Jan 24, 2021	The c.3457 C>T p.(His1153Tyr) variant detected in heterozygosity in the KCNH2 gene, is described in the literature in one patient with Long QT syndrome (PMID: 16414944) and in a case of sudden death (PMID: 26164358). This variant has been identified in population databases dbSNP (rs199473035), gnomAD with allele frequency (AF) of 0.00483%, exome aggregation consortium (ExAC) with AF of 0.00019 and absent in the database ESP. This rare variant is located in a moderately conserved residue in the distal C-terminus domain of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function (ClinVar ). Bioinformatics tools do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Therefore, it has been classified as a variant of uncertain clinical significance in ClinVar (Variation ID: 67497). Additionally, this variant was described in a German doctoral thesis in a male patient with atypical atrial flutter alternating with typical atrial flutter and paroxysmal atrial fibrillation. The functional characterization of the H1153Y channel variant in Xenopus oocytes showed a loss of function and no dominant negative effect on wild-type (WT) channels (Limberg, M., 2011). These results concur with a recent study that identified this H1153Y KCNH2 variant in a sudden arrhythmic death syndrome case. The study showed that the H1153Y variant causes a loss of KCNH2 channel function that reduces the current density leading to LQT2. (Farrugia, A. et al., 2021). -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces histidine with tyrosine at codon 1153 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 with cell culture system has shown that this variant causes a reduction in the channel current density, without apparent impact on channel trafficking to the cell membrane (PMID: 34502138). This variant has been reported in an individual affected with long QT syndrome (PMID: 16414944) and in an individual affected with sudden death (PMID: 26164358). This variant has been identified in 10/207056 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1153 of the KCNH2 protein (p.His1153Tyr). This variant is present in population databases (rs199473035, gnomAD 0.009%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16414944, 26164358, 34502138). ClinVar contains an entry for this variant (Variation ID: 67497). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 34502138). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2021

Reported in an individual with LQTS (Napolitano et al., 2005) and in an individual with sudden unexplained death while exercising (Farrugia et al., 2015); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67497; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32048431, 22581653, 26164358, 16414944, 19862833) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The p.H1153Y variant (also known as c.3457C>T), located in coding exon 15 of the KCNH2 gene, results from a C to T substitution at nucleotide position 3457. The histidine at codon 1153 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in long QT syndrome genetic testing cohorts (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Walsh R et al. Genet Med, 2021 Jan;23:47-58). Additionally, this alteration was detected in a sudden unexplained death cohort, and an in vitro assay showed it may impact protein function (Farrugia A et al. Forensic Sci. Int., 2015 Sep;254:5-11; Farrugia A et al. Int J Mol Sci, 2021 Aug;22:[ePub ahead of print]). 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 21, 2023

This missense variant replaces histidine with tyrosine at codon 1153 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 with cell culture system has shown that this variant causes a reduction in the channel current density, without apparent impact on channel trafficking to the cell membrane (PMID: 34502138). This variant has been reported in an individual affected with long QT syndrome (PMID: 16414944) and in an individual affected with sudden death (PMID: 26164358). This variant has been identified in 10/207056 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Congenital long QT syndrome

Other: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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.52

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.2

N;N

REVEL

Pathogenic

0.89

Sift

Benign

0.042

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

0.91

P;D

Vest4

0.34

MutPred

0.73

.;Gain of phosphorylation at H1153 (P = 0.0376);

MVP

0.96

MPC

0.59

ClinPred

0.28

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.57

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