Variant rs199472944 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):c.1841C>T(p.Ala614Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.85

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNH2_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) in NM_000238.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 7-150951552-G-A is Pathogenic according to our data. Variant chr7-150951552-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951552-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.1841C>T	p.Ala614Val	missense_variant	7/15	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.1841C>T	p.Ala614Val	missense_variant	7/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 10, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function and dominant negative are known mechanisms of disease for this gene. Loss of function and dominant negative are disease mechanisms for long QT syndrome 2 (MIM#613688), whereas gain of function is a disease mechanism for short QT syndrome 1 (MIM#609620). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (GeneReview). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in the pore forming region (PMID: 9721698). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in multiple patients with LQTS (ClinVar). (P) 1002 - Moderate functional evidence supporting abnormal protein function. In addition, functional studies show that this variant causes LQTS through dominant negative mechanism (PMID: 9721698, 21240260). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Jun 17, 2024	PP3moderate, PM2supporting, PP2, PM1, PS4moderate, PS3 -

Long QT syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 21, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19057127, 23303164, 25417810). 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"). ClinVar contains an entry for this variant (Variation ID: 29777). This missense change has been observed in individuals with long QT syndrome (PMID: 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the KCNH2 protein (p.Ala614Val). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 07, 2018	Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250692 control chromosomes. c.1841C>T has been reported in the literature in numerous individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, such as electrophysiological findings (Itzhaki_2011) and intracellular trafficking (Anderson_2006), both of which were impaired in the presence of the variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant exerts a dominant negative effect (Anderson et al., 2006; Sakaguchi et al., 2008; Itzhaki et al., 2011; Jou et al., 2013); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 29777); This variant is associated with the following publications: (PMID: 19057127, 22949429, 27555138, 19841300, 19716085, 18441445, 25417810, 18752142, 21703926, 21367833, 19070294, 31557540, 19843919, 23303164, 16432067, 25467552, 21240260, 9544837, 9927399, 9024139, 28316956, 28718902, 23864605, 15840476, 18808722, 15090700, 19996378, 11854117, 10560244, 21295269, 21185501, 10973849, 9693036, 9721698) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2021

The p.A614V pathogenic mutation (also known as c.1841C>T), located in coding exon 7 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1841. The alanine at codon 614 is replaced by valine, an amino acid with similar properties, and is located in the H5 intramembrane pore-forming region between transmembrane helices S5 and S6. This alteration has been identified in many unrelated patients with classic long QT syndrome (LQTS), reported to co-segregate with disease, and identified as a de novo mutation in LQTS probands without familial disease (Tanaka T et al. Circulation, 1997 Feb;95:565-7; Satler CA et al. Hum. Genet., 1998 Mar;102:265-72; Splawski I et al. Genomics, 1998 Jul;51:86-97; Priori SG et al. Circulation, 1999 Feb;99:529-33; Tenenbaum M et al. Isr. Med. Assoc. J., 2008 Nov;10:809-11; Kumakura M et al. J Clin Anesth, 2016 Sep;33:81-5). Numerous functional studies have demonstrated this alteration results in prolonged action-potential duration due to the loss of function of the IKr channel by deficient intracellular protein transport to the cell surface membrane (Nakajima T et al. Circ. Res., 1998 Aug;83:415-22; Sakaguchi T et al. J. Pharmacol. Sci., 2008 Dec;108:462-71; Itzhaki I et al. Nature, 2011 Mar;471:225-9; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:9024139;PMID:9544837;PMID:9693036;PMID:9927399;PMID:10560244;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19057127;PMID:19716085;PMID:19841300;PMID:19843919;PMID:10187793). 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

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;H;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

D;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.93

MutPred

0.93

.;Gain of methylation at K610 (P = 0.0983);.;

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

4.3

Varity_R

0.80

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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