7-150947864-C-T

Position:

chr7-150947864-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_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).

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

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11473337).

BS2

High AC in GnomAd4 at 39 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2707G>A	p.Gly903Arg	missense_variant	12/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.2707G>A	p.Gly903Arg	missense_variant	12/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1687G>A	p.Gly563Arg	missense_variant	8/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3540G>A		non_coding_transcript_exon_variant	10/13

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

GnomAD3 exomes

AF:

0.000143

AC:

AN:

126304

Hom.:

AF XY:

0.000202

AC XY:

AN XY:

69230

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000955

Gnomad4 AMR exome

AF:

0.0000854

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000428

Gnomad4 OTH exome

AF:

0.000191

GnomAD4 genome

AF:

0.000256

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

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

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2024	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 supports 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, 26582918, 36860515, 27000522, 37589201, 31557540) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2017	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. -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 15, 2023	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 an individual affected with sudden death, and in a family member who had prolonged QTc (PMID: 27000522). 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. -

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 31, 2022	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

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 28, 2022

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 an individual affected with sudden death, and in a family member who had prolonged QTc (PMID: 27000522). 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

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

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: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

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

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

MutationTaster

Benign

0.90

D;D;D

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

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