rs121912510

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_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. 15/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S818P) has been classified as Uncertain significance.

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

Publications

21 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
short QT syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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 chr7-150948995-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2773436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.

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 Pathogenic. ClinVar VariationId is 14432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.2453C>T	p.Ser818Leu	missense_variant	Exon 10 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251432

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

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

MVZ Martinsried, Medicover Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Long QT syndrome

Pathogenic:2

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.

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.

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

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

.;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

Benign

0.0

.;H

PhyloP100

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

Vest4

0.97

ClinPred

1.0

GERP RS

4.0

Varity_R

0.92

gMVP

0.96

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over