rs77331749

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

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).

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

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 -5 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 78 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2738C>T	p.Ala913Val	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.2738C>T	p.Ala913Val	missense_variant	12/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1718C>T	p.Ala573Val	missense_variant	8/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3571C>T		non_coding_transcript_exon_variant	10/13

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

GnomAD3 exomes

AF:

0.000400

AC:

AN:

120030

Hom.:

AF XY:

0.000411

AC XY:

AN XY:

65760

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:

0.00

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

Gnomad4 AFR exome

AF:

0.0000961

Gnomad4 AMR exome

AF:

0.0000293

Gnomad4 ASJ exome

AF:

0.0000412

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00182

Gnomad4 NFE exome

AF:

0.000577

Gnomad4 OTH exome

AF:

0.000507

GnomAD4 genome

AF:

0.000513

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 02, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 14, 2006	- -
Likely pathogenic, flagged submission	clinical testing	Blueprint Genetics	Apr 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 15, 2017	- -

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 09, 2016	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)." -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 20, 2021	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. -

Long QT syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 27, 2017	- -

Long QT syndrome 2/9, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 14, 2006

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 14, 2018

- -

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: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

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

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

MutationTaster

Benign

0.059

A;A;A

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

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

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