rs12720441

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000238.4(KCNH2):c.2350C>T(p.Arg784Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R784Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7O:1

Conservation

PhyloP100: 1.42

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_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000238.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 7-150950216-G-A is Pathogenic according to our data. Variant chr7-150950216-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14433.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Likely_pathogenic=2, not_provided=1}. Variant chr7-150950216-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2350C>T	p.Arg784Trp	missense_variant	9/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.2350C>T	p.Arg784Trp	missense_variant	9/15	1	NM_000238.4	P1	Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251062

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135716

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:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461538

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000306

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150868

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73546

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 784 of the KCNH2 protein (p.Arg784Trp). This variant is present in population databases (rs12720441, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 11997281, 15840476, 19841300, 22949429). ClinVar contains an entry for this variant (Variation ID: 14433). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 11997281, 25417810). 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	Aug 15, 2023	This missense variant replaces arginine with tryptophan at codon 784 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 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. -

Brugada syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 17, 2014

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Feb 21, 2022

- -

Long QT syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Long QT syndrome 2, acquired, susceptibility to

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Apr 23, 2002

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2020

The c.2350C>T (p.R784W) alteration is located in exon 9 (coding exon 9) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2350, causing the arginine (R) at amino acid position 784 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 01, 2023

This missense variant replaces arginine with tryptophan at codon 784 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 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. -

KCNH2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The KCNH2 c.2350C>T variant is predicted to result in the amino acid substitution p.Arg784Trp. This variant was reported in individuals with long QT syndrome (KCNH2 gene described as HERG, Yang et al. 2002. PubMed ID: 11997281; Tester et al. 2005. PubMed ID: 15840476; Table S2, Giudicessi et al. 2012. PubMed ID: 22949429). Functional analyses suggest that this variant may result in destabilization of the resultant protein and a reduction in channel activity, and authors of one study speculated that this could be a mild variant (Yang et al. 2002. PubMed ID: 11997281; Anderson et al. 2014. PubMed ID: 25417810). However, this variant has also been documented in the general population and in a cohort of asymptomatic individuals with no prior history of cardiovascular events (Table S1, Chen et al. 2018. PubMed ID: 30662450; Lacaze et al. 2021. PubMed ID: 34135346). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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:11997281;PMID:14760488;PMID:15840476;PMID:19841300). 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

0.99

CardioboostArm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.7

D;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.97

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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