chr7-150951679-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):c.1714G>A(p.Gly572Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,354 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G572C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.54

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 18 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150951679-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 7-150951679-C-T is Pathogenic according to our data. Variant chr7-150951679-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951679-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.1714G>A	p.Gly572Ser	missense_variant	Exon 7 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.1714G>A	p.Gly572Ser	missense_variant	Exon 7 of 15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000240

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:

0.00

Gnomad4 OTH

AF:

0.00

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:3

Dec 15, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.1714G>A (p.Gly572Ser) variant is a missense variant. Across a selection of the available literature, this variant has been identified in a heterozygous state in at least seven unrelated individuals with long QT syndrome (Fodstad et al. 2004; Tester et al. 2005; Kapplinger et al. 2009; Zhao et al. 2009; Chae et al. 2017). Control data are unavailable for the p.Gly572Ser variant, which is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Co-expression of the p.Gly572Ser variant and wild type KCNH2 cDNA in continuous cell lines demonstrated that the p.Gly572Ser variant channel did not undergo glycosylation within the Golgi and has a dominant negative effect on the trafficking of KCNH2 to the cellular membrane, causing its retention in the ER and Golgi, and thereby reduction of channel activity with a reduction in current density of 90% compared to wild type (Anderson et al. 2006; Zhao et al. 2009; Liu et al. 2016). Based on the collective evidence and the application of the ACMG criteria, the p.Gly572Ser variant is classified as pathogenic for long QT syndrome. -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4+PP4+PP3_Strong+PP2 -

not provided

Pathogenic:3

Jun 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported multiple times in individuals with LQTS in the published literature and referred for genetic testing at GeneDx (Fodstad et al., 2004; Giudicessi et al., 2012; Ebrahim et al., 2017); Published functional studies demonstrate a dominant-negative effect that leads to a loss of normal potassium ion channel function (Anderson et al., 2006; Zhao et al., 2009; Jou et al., 2013; Mahati et al., 2016); 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; This variant is associated with the following publications: (PMID: 28082916, 19490267, 23303164, 27803431, 22949429, 28532774, 30850667, 31737537, 32383558, 34570182, 15176425, 16432067) -

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Gly572Ser This variant has been reported in multiple cases of long QT syndrome. Takashi et al (2004) reported the variant in at least one case of long QT syndrome (only the abstract was available with minimal data included). Tester et al (2005) reported this variant in their compendium of variants identified in patients referred to the Mayo Clinic's Sudden Death Genomics Laboratory for long QT genetic testing. They observed the variant in two presumably unrelated patients (unclear); no phenotypic data was provided. Horigome et al (2009) reported the variant in female child who presented with Torsades, AV block, and a QTc of 520 ms an was diagnosed with long QT syndrome with as a neonate (this case my overlap with the one reported by Takashi, thought Takashi is not in the author list of this publication). Kotta et al (2010) reported the variant in on individual their Greek cohort of patients with long QT syndrome. No segregation or functional data was provided in any of these reports. Two other variants have been reported at the same codon in association with long QT syndrome. Splawski et al (2000) report p.Gly572Cys in association with long QT syndrome. Larsen et al (2000) reported three family members with long QT syndrome and p.Gly572Arg in KCNH2. Lian et al (2010) studied the biophysical phenotype of p.Gly572Arg and concluded it generates a trafficking-deficient phenotype with a dominant negative effect. In silico analysis with Polyphen 2 predicts the p.Gly572Ser to be probably damaging. Codon 572 is highly conserved across species and isoforms. The variant is in the S5 segment, in the extracellular space, very close to the pore. Tester et al (2005) did not observe p.Gly572Ser in 744 control individuals from four different ethnic groups and Kotta et al (2010) did not see it in 100 control individuals of Greek origin. Control data was not published by the other groups. Based on these data it is very likely that this variant causes long QT syndrome. -

Long QT syndrome

Pathogenic:1

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 572 of the KCNH2 protein (p.Gly572Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 15176425, 19490267, 22949429, 27803431). ClinVar contains an entry for this variant (Variation ID: 67248). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 16432067, 19490267, 23303164, 27803431, 28082916). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Nov 21, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G572S pathogenic mutation (also known as c.1714G>A), located in coding exon 7 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1714. The glycine at codon 572 is replaced by serine, an amino acid with similar properties. This alteration has been reported in multiple unrelated individuals with long QT syndrome (Fodstad H et al. Ann Med. 2004; 36 Suppl 1:53-63; Tester DJ et al. Heart Rhythm. 2005; 2(5):507-17; Chung SK et al. Heart Rhythm. 2007; 4(10):1306-14; Berge KE et al. Scand J Clin Lab Invest. 2008; 68(5):362-8; Horigome H et al. Circ Arrhythm Electrophysiol. 2010; 3(1):10-7; Hedley PL et al. Cardiovasc J Afr. 2013; 24(6):231-7). This alteration has also been reported to co-segregate with prolonged QTc interval or long QT syndrome phenotype in families (Horie M et al. Circ J 2007;71 Suppl A:A50-3; Ohno S et al. Hum Mutat. 2009; 30(4):557-63; Aziz PF et al, Heart Rhythm. 2010; 7(6):781-5). In vitro functional studies have reported this alteration to result in abnormal channel trafficking and dominant negative effect leading to loss of normal KCNH2 ion channel function (Anderson CL et al. Circulation. 2006; 113(3):365-73; Zhao JT et al. J Cardiovasc Electrophysiol. 2009; 20(8):923-30; Jou CJ et al. Circ Res. 2013; 112(5):826-30; Liu L et al. Front Physiol, 2016 Dec;7:650). In addition, multiple alterations affecting the same amino acid (p.G572C (c.1714G>T), p.G572R (c.1714G>C), p.G572D (c.1715G>A) and p.G572V (c.1715G>T)) have also been reported in association with long QT syndrome (Splawski I et al. Genomics. 1998; 51(1):86-97; Larsen LA et al. Clin Genet. 2000; 57(2):125-30; Napolitano C et al. JAMA. 2005; 294(23):2975-80; Kapplinger JD et al. Heart Rhythm. 2009; 6(9):1297-303). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, p.G572S is interpreted as a disease-causing mutation. -

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Pathogenic:1

Dec 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15176425;PMID:15840476;PMID:16432067;PMID:16831322;PMID:17905336;PMID:18752142;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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

2.0

.;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.9

D;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0020

D;D;.

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.83

.;Gain of disorder (P = 0.0657);.;

MVP

1.0

MPC

2.2

ClinPred

0.99

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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