NM_000238.4:c.2738C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_000238.4(KCNH2):c.2738C>T(p.Ala913Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,524,188 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. A913E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00052 ( 1 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:5O:1

Conservation

PhyloP100: 0.134

Publications

25 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: Likely_benign. The variant received -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.37117094).

BP6

Variant 7-150947833-G-A is Benign according to our data. Variant chr7-150947833-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14443.

BS2

High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2738C>T	p.Ala913Val	missense_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.2738C>T	p.Ala913Val	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000400

AC:

AN:

120030

AF XY:

0.000411

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:

0.00226

Gnomad NFE exome

AF:

0.000765

Gnomad OTH exome

AF:

0.000268

GnomAD4 exome

AF:

0.000523

AC:

717

AN:

1372084

Hom.:

Cov.:

AF XY:

0.000534

AC XY:

361

AN XY:

676160

show subpopulations

African (AFR)

AF:

0.0000961

AC:

AN:

31208

American (AMR)

AF:

0.0000293

AC:

AN:

34088

Ashkenazi Jewish (ASJ)

AF:

0.0000412

AC:

AN:

24282

East Asian (EAS)

AF:

0.00

AC:

AN:

35556

South Asian (SAS)

AF:

0.00

AC:

AN:

77284

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

34698

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4042

European-Non Finnish (NFE)

AF:

0.000577

AC:

620

AN:

1073722

Other (OTH)

AF:

0.000507

AC:

AN:

57204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

114

152

190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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

AF:

0.000513

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41416

American (AMR)

AF:

0.000262

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000431

Hom.:

Bravo

AF:

0.000370

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:2Uncertain:2

Apr 30, 2015

Blueprint Genetics

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Nov 14, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 02, 2023

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KCNH2 c.2738C>T (p.Ala913Val) is a missense variant that has been reported in seven studies in which it is found in a heterozygous state in a total of eleven individuals with either confirmed or suspected long QT syndrome (Tester et al. 2005; Vatta et al. 2006; Kapplinger et al. 2009; Lieve et al. 2013; Trolle et al. 2013; Christiansen et al. 2014; Webster et al. 2019). The p.Ala913Val variant was also detected in a compound heterozygous state in one individual with long QT syndrome who also carried a missense variant in the SCN5A gene. This individual's unaffected father and unaffected sibling also carried the p.Ala913Val variant in a heterozygous state (Hoshi et al. 2015). An individual with atrial fibrillation and mitral valve regurgitation was also reported to be heterozygous for the variant (Gregers et al. 2017). The p.Ala913Val variant was absent from 2,964 control chromosomes (Kapplinger et al. 2009; Christiansen et al. 2014) but is reported at a frequency of 0.002390 in the European (Finnish) population of the Genome Aggregation Database, which includes one homozygote. When the KCNH2 protein bearing the p.Ala913Val variant was expressed in HEK293 cells, electrophysiological measurements showed that there was a 37% reduction in the tail current when compared to wildtype protein. The authors stated that this variant alone was not sufficient to cause long QT syndrome (Hoshi et al. 2015). Gregers et al. (2017) performed similar studies indicating that the variant resulted in a mild gain of function rather than a loss of function. Based on the collective evidence and the application of ACMG criteria, the p.Ala913Val variant is classified as a variant of uncertain significance for long QT syndrome. -

Nov 15, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:2

Aug 09, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The KCNH2 c.2738C>T (p.Ala913Val) variant is located in the C-terminus causing a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this variant. The variant of interest was not found in controls (ExAC, ESP, 1000 Gs, or publication controls). Multiple publications cite the variant in affected individuals including the variant to co-occur with a known CAV3 mutation, T78M, along with another KCNH2 variant, S654V (not yet scored), along with evidence for lack of cosegregation within one family (Hoshi_2015). Functional studies have implicated that the variant has a mild affect on wild type function (Hoshi_2015), along with the authors further suggested that the variant alone does not cause disease (Hoshi_2015). In addition, a recent independent study performed by Van Driest_2016, in which expert reviews were performed by three independent clinical laboratories to assess classification of this variant, two out of the three laboratories indicated the variant to not be pathogenic. Furthermore, multiple reputable clinical laboratories have provided conflicting classifications, "uncertain significance," "likely pathogenic," or "pathogenic." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -

Jan 20, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KCNH2 c.2738C>T; p.Ala913Val variant (rs77331749) is reported in the literature in several individuals affected with long QT syndrome (Hoshi 2015, Kapplinger 2009, Tester 2005, Vatta 2006). This variant is found in the Finnish European population with an overall allele frequency of 0.24% (22/9204 alleles, including one homozygote) in the Genome Aggregation Database. The alanine at codon 913 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.502). Functional studies indicate a modestly reduced current of the variant protein compared to wildtype, although it is uncertain if this difference is clinically significant (Hoshi 2015). Although the population frequency of this variant is inconsistent with disease, since a low penetrance effect cannot be ruled out, the clinical significance of the p.Ala913Val variant is uncertain at this time. References: Hoshi M et al. Polygenic Case of Long QT Syndrome Confirmed through Functional Characterization Informs the Interpretation of Genetic Screening Results. HeartRhythm Case Rep. 2015 Jul 1;1(4):201-205. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. Vatta M et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006 Nov 14;114(20):2104-12. -

Aug 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 08, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar with conflicting classifications (ClinVar Variant ID# 14443; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19716085, 24606995, 22245016, 17060380, 26746457, 30704477, 31395126, 25417810, 26213684, 23936059, 26383259, 15840476, 23631430, 14661677, 16540748, 28416588, 32048431, 31737537) -

Long QT syndrome

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome 2/9, digenic

Pathogenic:1

Nov 14, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Cardiovascular phenotype

Benign:1

Jun 02, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cardiac arrhythmia

Benign:1

Apr 14, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:15840476;PMID:19716085). 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

0.078

CardioboostArm

Benign

0.00016

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.37

T;T

MetaSVM

Uncertain

0.091

MutationAssessor

Benign

0.0

.;N

PhyloP100

0.13

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.85

N;N

REVEL

Uncertain

0.50

Sift

Benign

0.52

T;T

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;B

Vest4

0.16

MutPred

0.77

.;Loss of relative solvent accessibility (P = 0.0071);

MVP

1.0

MPC

0.17

ClinPred

0.033

GERP RS

0.11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.54

Mutation Taster

=89/11

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over