NM_000238.4:c.2453C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):c.2453C>T(p.Ser818Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S818P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 18 ACMG points.

PM1

In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150948996-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 7-150948995-G-A is Pathogenic according to our data. Variant chr7-150948995-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150948995-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2453C>T	p.Ser818Leu	missense_variant	Exon 10 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 link	c.2453C>T	p.Ser818Leu	missense_variant	Exon 10 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 link	c.1433C>T	p.Ser478Leu	missense_variant	Exon 6 of 11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 link	n.3286C>T		non_coding_transcript_exon_variant	Exon 8 of 13

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251432

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:2

Sep 15, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 10, 2019

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Pathogenic:2

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 818 of the KCNH2 protein (p.Ser818Leu). This variant is present in population databases (rs121912510, gnomAD 0.003%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 10086971, 17088455, 18441445, 23158531, 26669661). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14432). 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: 10996323, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic. -

Sep 18, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2453C>T (p.Ser818Leu) variant in KCNH2 gene, that encodes for potassium voltage-gated channel subfamily H member 2, has been identified in numerous (>30) individuals affected with long QT syndrome (LQTS) (PMID: 21440677, 18441445, 23158531, 27920829, 32893267, 26669661), including one individual with de novo occurrence (PMID: 10086971). Functional studies using Xenopus oocytes, HEK293 cells and rescue experiments on morpholino kcnh2-knockdown zebra fish revealed that KCNH2-S818L mutant can cause significantly reduced current amplitude, trafficking deficiency, reduced membrane expression and channel dysfunction (PMID: 10996323, 16432067, 26958806, 23303164). This variant is located in the C-terminal cyclic nucleotide binding domain and this domain is characterized by high enrichment of case variants and >95% probability of pathogenicity (PMID: 32893267). In-silico computational prediction tools suggest that the p.Ser818Leu variant may have deleterious effect on the protein function (REVEL score: 0.97). This variant is rare (4/1614168 chromosomes; 0.0002478%) in the general population database, gnomAD (v4.1.0), and classified as pathogenic by multiple submitters in ClinVar (ID: 14432). Therefore, the c.2453C>T (p.Ser818Leu) variant in the KCNH2 gene is classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:2

Mar 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S818L pathogenic mutation (also known as c.2453C>T), located in coding exon 10 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2453. The serine at codon 818 is replaced by leucine, an amino acid with dissimilar properties. This variant was described in a confirmed de novo case with torsades de pointes and syncope, as well as in her asymptomatic young daughter with prolonged QTc (Berthet M et al. Circulation, 1999 Mar;99:1464-70). This variant has also been reported in additional long QT syndrome cohorts (Nagaoka I et al. Circ. J., 2008 May;72:694-9; Crotti L et al. J. Am. Coll. Cardiol., 2012 Dec;60:2515-24; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95). Functional studies have demonstrated trafficking deficiency with significant reduction in potassium channel function (Anderson CL et al. Circulation, 2006 Jan;113:365-73; Perry MD et al. J. Physiol. (Lond.), 2016 07;594:4031-49). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 16, 2022

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia

Pathogenic:1

Oct 10, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 818 in the KCNH2 protein. This variant is found within the highly conserved cyclic nucleotide binding domain (aa 742-842). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes trafficking defects resulting in reduced membrane expression and impaired channel function (PMID: 10996323, 16432067, 23303164, 26958806, 31557540). This variant has been reported in over twenty individuals affected with long QT syndrome (PMID: 10086971, 18441445, 21440677, 23158531, 26669661, 27920829, 32893267, 35253369, 36102233) and has been observed to be a de novo occurrence in at least one of the probands (PMID: 10086971). This variant has also been reported in an individual affected with sudden cardiac death and idiopathic left ventricular hypertrophy (PMID: 32011662). Two relatives of this proband also carried this variant, who were both affected with long QT syndrome. This variant has been identified in 1/251432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Congenital long QT syndrome

Other:1

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10086971;PMID:10996323;PMID:11222472;PMID:16432067;PMID:16831322;PMID:18441445). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

.;H

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.86

.;Loss of disorder (P = 0.0089);

MVP

0.99

MPC

2.1

ClinPred

1.0

GERP RS

4.0

Varity_R

0.92

gMVP

0.96

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