7-150947864-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_000238.4(KCNH2):c.2707G>A(p.Gly903Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000338 in 1,530,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1O:1

Conservation

PhyloP100: 4.55

Publications

9 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 -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 26 uncertain in NM_000238.4

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=0.11473337).

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2707G>A	p.Gly903Arg	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.2707G>A	p.Gly903Arg	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.0208

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000143

AC:

AN:

126304

AF XY:

0.000202

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.0000837

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.000256

GnomAD4 exome

AF:

0.000347

AC:

478

AN:

1377834

Hom.:

Cov.:

AF XY:

0.000372

AC XY:

253

AN XY:

679646

show subpopulations

African (AFR)

AF:

0.0000955

AC:

AN:

31402

American (AMR)

AF:

0.0000854

AC:

AN:

35128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24838

East Asian (EAS)

AF:

0.00

AC:

AN:

35630

South Asian (SAS)

AF:

0.00

AC:

AN:

78468

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4062

European-Non Finnish (NFE)

AF:

0.000428

AC:

461

AN:

1076418

Other (OTH)

AF:

0.000191

AC:

AN:

57488

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000256

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000299

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000111

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in patients with LQTS and sudden death referred for genetic testing at GeneDx and in published literature (PMID: 19716085, 34002542, 27000522); One in vitro functional study suggests p.(G903R) may alter the kinetic properties of potassium channel; however, another in vitro functional study suggests this variant has minimal effect on channel function (PMID: 34002542, 31557540); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28988457, 19716085, 26746457, 32048431, 31737537, 30847666, 34002542, 36860515, 27000522, 37589201, 31557540, 37937776) -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:2

Jan 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in 3 patients referred for LQTS genetic testing. The variant is not in ExAC. It is classified with 1 star in ClinVar as VUS by GeneDx. -

Apr 26, 2024

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: KCNH2 c.2707G>A (p.Gly903Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 126304 control chromosomes. The observed variant frequency is approximately 1.43 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing long QT syndrome (0.0001), suggesting that the variant may be benign. c.2707G>A has been reported in the literature in at least 5 individuals who underwent genetic testing for arrhythmia, at least one individual with epilepsy, and at least one individual who died suddenly as well as a family member with a prolonged QT interval (eg., Kapplinger_2009, Cann_2016, Marschall_2019, van Lint_2019, Soh_2021). However, these data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function; one study demonstrates the variant has a mild effect on channel deactivation kinetics, however both studies conclude there is no effect on protein expression levels when compared to wild type (Ng_2020, Soh_2021). The following publications have been ascertained in the context of this evaluation (PMID: 27000522, 19716085, 31737537, 31557540, 34002542, 30847666). ClinVar contains an entry for this variant (Variation ID: 67428). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Long QT syndrome

Uncertain:2

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with arginine at codon 903 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). Functional studies have shown that this variant does not change protein expression levels and has no or a mild impact on the potassium channel function (PMID: 31557540, 34002542). This variant has been reported in three individuals referred for long QT syndrome genetic testing (PMID: 19716085) and in an individual affected with epilepsy (PMID: 34002542). This variant has also been reported in individuals affected with sudden death, and in family members who had prolonged QTc interval (PMID: 27000522, 37449562, 37589201). This variant has been reported at a frequency of 0.097% in a large population study, demonstrating no significant correlation with prolonged QTc intervals in the Icelandic population (PMID: 37449562). This variant has been identified in 19/157684 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. -

Jan 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 903 of the KCNH2 protein (p.Gly903Arg). This variant is present in population databases (rs199473669, gnomAD 0.02%). This missense change has been observed in individual(s) with long QT syndrome or Brugada syndrome (PMID: 19716085, 27000522). ClinVar contains an entry for this variant (Variation ID: 67428). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNH2 function (PMID: 31557540). 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. -

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

Uncertain:2

Oct 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2022

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2707G>A variant has previously been reported in literature as Variant of Uncertain Significance [PMID: 19716085, 28988457, 31737537, 30847666, 32048431] and it has also been deposited in ClinVar [ClinVar ID: 67428] as Variant of Uncertain Significance by multiple submitters. The c.2707G>A variant is observed in 127 alleles (~0.027% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant inthe populations represented in those databases, which might include individuals with cardiac phenotypes. The c.2707G>A variant is located in exon 12 of this 15-exon gene, and predicted to replace an evolutionarily conserved glycine amino acid with arginine at position 903 in the second disordered region of the encoded protein [UniProtKB ID: Q12809]. Patch-clamp assays with transfected HEK293 cell lines demonstrated modestly accelerated rates of channel deactivation for p.(Gly903Arg) variant compared to wild-type allele [PMID: 31557540]. In silico predictions are also moderately in favor of damaging effect for the p.(Gly903Arg) variant (CADD v1.6 =23.3, REVEL = 0.745). Based on available evidence this c.2707G>A p.(Gly903Arg) variant identified in KCNH2 is classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia

Uncertain:1

Mar 31, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with arginine at codon 903 of the KCNH2 protein. This variant is located within the conserved cytoplasmic domain (a.a. 660-1159) of the KCNH2 protein. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. Functional studies have shown that this variant does not change protein expression levels and has no or a mild impact on the potassium channel function (PMID: 31557540, 34002542). This variant has been reported in three individuals referred for long QT syndrome genetic testing (PMID: 19716085) and in an individual affected with epilepsy (PMID: 34002542). This variant has also been reported in individuals affected with sudden death, and in family members who had prolonged QTc interval (PMID: 27000522, 37449562, 37589201). This variant has been reported at a frequency of 0.097% in a large population study, demonstrating no significant correlation with prolonged QTc intervals in the Icelandic population (PMID: 37449562). This variant has been identified in 19/157684 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. -

Cardiovascular phenotype

Benign:1

Sep 06, 2022

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. -

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: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

0.14

CardioboostArm

Benign

0.0049

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.11

T;T

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.7

.;L

PhyloP100

4.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.55

N;N

REVEL

Pathogenic

0.74

Sift

Benign

0.14

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.93

P;B

Vest4

0.57

MutPred

0.69

.;Gain of MoRF binding (P = 0.0295);

MVP

0.99

MPC

0.20

ClinPred

0.13

GERP RS

5.0

Varity_R

0.39

gMVP

0.73

Mutation Taster

=5/95

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over