Variant 7-150951643-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):c.1750G>A(p.Gly584Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,876 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 7.72

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_000238.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 7-150951643-C-T is Pathogenic according to our data. Variant chr7-150951643-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951643-C-T 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.1750G>A	p.Gly584Ser	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.1750G>A	p.Gly584Ser	missense_variant	7/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251412

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135908

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000138

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000363

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 2

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 21, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Sep 29, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 11, 2024	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 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 using patch clamp assays in transfected Chinese hamster ovary (CHO) cells and Xenopus oocytes suggest that the G584S mutant channel causes a loss of the rapid delayed rectifier current due to trafficking and gating defects (Zhao et al., 2009; Perry et al., 2016); Reported as a pathogenic/likely pathogenic variant in ClinVar (ClinVar Variant ID#67261; ClinVar); This variant is associated with the following publications: (PMID: 21440677, 27807201, 24606995, 22581653, 31447099, 15176425, 20659946, 20566482, 22949429, 25417810, 25649125, 26187847, 26669661, 19490267, 26958806, 19716085, 10862094, 23098067, 15840476, 10973849, 10483966, 19841300, 31358886, 28431243, 32048431, 34319147, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 17, 2019	PS3_Supporting, PS-Moderate, PP2, PP3, PP1_Moderate, PM1 -

Congenital long QT syndrome

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2019	The p.Gly584Ser variant in KCNH2 has been reported in 4 individuals with long QT syndrome, segregated with disease in at least 11 affected relatives from 2 families (Swan 1999, Laitinen 2000, Zhao 2009, Giudicessi 2012, and Li 2015), and has also been reported by other clinical laboratories in ClinVar (Variation ID: 67261). In vitro functional studies provide some evidence that the p.Gly584Ser variant may impact protein function (Zhao 2009). This variant was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pathogenic. -
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:10483966;PMID:10862094;PMID:10973849;PMID:15840476;PMID:19490267;PMID:19716085;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Short QT syndrome type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 11, 2024

- -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2023

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 disruptive. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 584 of the KCNH2 protein (p.Gly584Ser). This variant is present in population databases (rs199473428, gnomAD 0.002%). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 10862094, 10973849, 19490267, 22949429, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67261). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 19490267). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2023

The p.G584S variant (also known as c.1750G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1750. The glycine at codon 584 is replaced by serine, an amino acid with similar properties, and is located in the S5/pore transmembrane spanning region. This alteration has been detected in long QT syndrome (LQTS) cohorts, a sudden cardiac arrest/death cohort, and cohorts referred for LQTS genetic testing with varying levels of clinical detail (Splawski I et al. Circulation. 2000;102:1178-85; Kapa S et al. Circulation. 2009;120:1752-60; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Christiansen M et al. BMC Med Genet. 2014;15:31; Li MH et al. Hum Genomics. 2015;9:15; Nakajima T et al. Circ J. 2015;79(6):1185-92). This alteration has been reported to segregate with disease in a family with symptomatic individuals and members with moderate QTc prolongation where, overall, carriers had longer QT intervals than non-carriers; however, some individuals with QT prolongation were not indicated as carriers of this alteration, suggesting that this alteration is associated with reduced phenotypic penetrance (Kerr SM et al. Sci Rep, 2019 Jul;9:10964; Swan H et al. J Am. Coll Cardiol. 1999;34:823-9; Laitinen P et al. Hum Mutat. 2000;15:580-1). In vitro functional studies have suggested this alteration may have some impact on channel function or protein trafficking (Zhao JT et al. J Cardiovasc Electrophysiol. 2009;20:923-30; Perry MD et al. J Physiol Lond. 2016;594:4031-49). Internal analysis indicates this alteration may be structurally disruptive (Wang W et al. Cell. 2017;169(3):422-430.e10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Feb 10, 2016

- -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 14, 2019

This missense variant replaces glycine with serine at codon 584 in the extracellular linker region between transmembrane domain S5 and pore-forming region of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that the mutant protein carrying this variant traffics to the cell membrane normally but has moderate impact on the channel function (PMID: 19490267, 26958806). This variant has been reported to segregate with long QT syndrome in a large multigenerational family (PMID: 19490267). This variant has also been reported in multiple unrelated individuals affected with long QT syndrome (PMID: 10862094, 10973849, 22949429, 23098067, 24606995, 25925977). This variant has been identified in 2/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

.;D;D

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.84

.;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.9

D;D;.

REVEL

Pathogenic

0.87

Sift

Benign

0.28

T;T;.

Sift4G

Benign

0.24

T;T;T

Polyphen

0.92

P;D;.

Vest4

0.93

MVP

0.99

MPC

2.1

ClinPred

0.98

GERP RS

4.4

Varity_R

0.54

gMVP

0.97

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