rs36210422

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_000238.4(KCNH2):c.526C>T(p.Arg176Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,466,372 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:4O:2

Conservation

PhyloP100: 1.14

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 Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

BS2

High AC in GnomAd4 at 53 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.526C>T	p.Arg176Trp	missense_variant	Exon 4 of 15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNH2	ENST00000262186.10 link	c.526C>T	p.Arg176Trp	missense_variant	Exon 4 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000532957.5 link	n.749C>T		non_coding_transcript_exon_variant	Exon 4 of 9	2
KCNH2	ENST00000684241.1 link	n.1359C>T		non_coding_transcript_exon_variant	Exon 2 of 13

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000662

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000633

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000324

AC:

AN:

77224

Hom.:

AF XY:

0.000270

AC XY:

AN XY:

44402

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:

0.00105

Gnomad NFE exome

AF:

0.000656

Gnomad OTH exome

AF:

0.000444

GnomAD4 exome

AF:

0.000324

AC:

426

AN:

1314244

Hom.:

Cov.:

AF XY:

0.000346

AC XY:

224

AN XY:

647814

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:

0.0000139

Gnomad4 FIN exome

AF:

0.000918

Gnomad4 NFE exome

AF:

0.000367

Gnomad4 OTH exome

AF:

0.000202

GnomAD4 genome

AF:

0.000348

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000662

Gnomad4 NFE

AF:

0.000633

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000530

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000171

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:4Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 2

Uncertain:4Benign:1Other:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2015

Blueprint Genetics

Significance: risk factor

Review Status: flagged submission

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 09, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNH2 c.526C>T p.(Arg176Trp) missense has been widely reported in association with long QT syndrome (LQTS) and described as a founder variant in the Finnish population. Across a selection of the available literature, the variant has been identified in a heterozygous state in at least 100 of approximately 3,000 patients with LQTS or prolonged QTc intervals, and a significant increase in QTc in carriers compared to non-carriers has been demonstrated (Swan et al. 1999; Laitinen et al. 2000; Ackerman et al. 2003; Tester et al. 2006; Fodstad et al. 2004; Fodstad et al. 2006; Marjamaa et al. 2009; Giudicessi et al. 2012; Lahtinen et al. 2013; Koponen et al. 2015). Notably, however, many individual carriers remain asymptomatic and have QTc intervals that do not meet diagnostic criteria for LQTS. The variant has also been proposed to act as a risk factor for cardiac events; Koponen et al. (2018) reported a hazard ratio of cardiac events at age 18-40 years, before initiation of beta-blocker therapy, of 5.87 (95% CI 2.89-11.9). The p.(Arg176Trp) variant has also been identified in a compound or double heterozygous state with a second pathogenic variant, suggesting it may exert a modifying effect. This variant is reported at a frequency of 0.001231 in the European (Finnish) population of the Genome Aggregation Database (version 2.1.). This frequency is higher than expected given the known prevalence, penetrance, and inheritance of LQTS. Functional studies of the p.(Arg176Trp) variant have provided conflicting results. When the variant was expressed independently in COS-7 cells, a reduction in current density and tail current to approximately 25% of wildtype and a slight acceleration of deactivation kinetics was observed (Fostad et al. 2006). However, when co-expressed with wildtype, the current reduction was no longer present, suggesting the absence of a dominant-negative effect. In cardiomyocytes derived from iPS cells from an asymptomatic carrier, the rapid delayed potassium channel density was significantly reduced, and at low beating rates, the repolarization time was significantly prolonged compared to that in control cells (Lahti et al. 2012). However, no positive control variants were included and the potential influence of additional variants in the carrier from whom the cells originated was not excluded. In addition, in zebrafish, both wildtype and R176W KCNH2 showed a similar ability to rescue the effect of morpholino-mediated gene knockdown, suggesting a benign effect of the variant (Jou et al. 2013). This variant affects a conserved residue but is not located in a mutational hotspot or functional domain. While missense variants are a known mechanism of disease for LQTS, benign missense variants have been reported, including in the region surrounding position 176. Based on the collective evidence, the c.526C>T p.(Arg176Trp) variant is classified as a variant of uncertain significance for long QT syndrome. -

May 31, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2Benign:1

Oct 31, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.526C>T (p.Arg176Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 80198 control chromosomes. The observed variant frequency is approximately 2.83 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Long QT Syndrome phenotype (0.00012), strongly suggesting that the variant is benign. c.526C>T has been reported in the literature in individuals undergoing limited gene to multigene panel testing for Long QT Syndrome/Arrhythmia and continues to be reported as a VUS/risk variant that is enriched in patients referred for diagnostic LQTS gene testing but lacking a molecular diagnosis (panel-negative) (example, Kapa_2009, Koponen_2015, Laitinen_2000, Mank-Seymour_2006, Marjamaa_2009, Swan_1999, van Lint_2019, Vatta_2021, Kozek_2021). These report(s) do not provide unequivocal conclusions about a penetrant inherited association of the variant with Long QT Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (KCNQ1 c.1766G>A, p.Gly589Asp; KCNQ1 IVS7-2A>G), providing supporting evidence for a benign role (example, Koponen_2015, Fodstad_2006). However, the possibility of this variant exerting an additional in vivo phenotypic effect when present simultaneously with an apparent LQTS-causing mutation has also been proposed (Fodstad_2006). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant as indicated by normal repolarization in the kcnh2-knockdown embryonic zebrafish (example, Jou_2013). The following publications have been ascertained in the context of this evaluation (PMID: 14661677, 16754261, 23303164, 19841300, 26063740, 34309407, 10862094, 17161064, 19160088, 10483966, 33517668, 30847666). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=9, likely benign, n=2, risk factor, n=1). Based on the evidence outlined above, the variant in isolation was classified as likely benign. -

Nov 10, 2015

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 8 papers, in affected and unaffected individuals, with some suggesting benign, others pathogenic and one calling it a Finnish founder mutation. It is classified in ClinVar with 1 star as Likely benign by Invitae, VUS by GeneDx and risk factor by Blueprint genomics. It is not present in ExAC but has a max MAF in gnomAD of 0.12% (10/8048 Finnish alleles and 33 european alleles). Note from April 2016: This variant has not undergone full assessment. The following are preliminary notes: conflicting reports. Also very difficult to do the full NVA because most papers we do not have access at. Possibly upgrade to VUS4? OB 12/28/15: VUS4 based on the full NVA. Heidi agrees that it is VUS4 and does not meet criteria for reporting. -

Long QT syndrome

Uncertain:2Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2022

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Risk factor for disease development: PS4; PP1_strong; PS3_mod; PP2; PP3; BS1; BS2 -

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: BS1, PP2, PP3 -

not provided

Uncertain:1Benign:1Other:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNH2: PP2, PP3 -

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 in the following publications (PMID:10483966;PMID:10862094;PMID:14661677;PMID:16818214;PMID:17161064;PMID:19160088;PMID:19841300;PMID:19862833;PMID:16754261;PMID:22052944;PMID:22429796). -

Dec 26, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with LQTS but also present in asymptomatic individuals, control individuals, and individuals who harbor additional cardiogenetic variants referred for genetic testing at GeneDx or in published literature (PMID: 10483966, 10862094, 14661677, 17161064, 16754261, 22067087, 23098067, 24606995, 26063740, 28003625); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Electrophysiological studies suggest the presence of the p.(R176W) variant may lead to changes in HERG channel function under various experimental conditions; however, other functional studies suggest that this variant has a benign effect (PMID: 22052944, 16754261, 23303164, 34002542); This variant is associated with the following publications: (PMID: 14661677, 22067087, 25351510, 25467552, 32383558, 22429796, 17161064, 19160088, 24606995, 16754261, 16818214, 17222736, 23098067, 23651034, 22677073, 26063740, 27026928, 28003625, 27650965, 22949429, 28255936, 15176425, 29622001, 15541256, 19673885, 10862094, 19841300, 19862833, 21244686, 20875080, 21956039, 23193492, 22402074, 22659597, 23631430, 25554238, 26749013, 27064559, 30847666, 34002542, 23303164, 28988457, 32048431, 31539150, 31737537, 33517668, 33435129, 34426522, 32659924, 22052944, 10483966, 35640313, 34841674, 35911527, 34309407, 35103483, 37128929, 36860515, 36597672, 36693943, 38219013, 37324772, ZhangH2023[Abstract], 38254962, 36269083, 37614113, 38014677) -

Short QT syndrome type 1

Uncertain:1

Jan 21, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3. -

See cases

Uncertain:1

Apr 08, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM2,PP3 -

Cardiovascular phenotype

Uncertain:1

Aug 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R176W variant (also known as c.526C>T), located in coding exon 4 of the KCNH2 gene, results from a C to T substitution at nucleotide position 526. The arginine at codon 176 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified in subjects with long QT syndrome (LQTS) and has been reported as a possible Finnish founder mutation (Swan H, J. Amer. Coll. Cardiol. 1999;34(3):823-9; Laitinen P, Hum. Mutat. 2000; 15(6):580-1; Fodstad H, Ann. Med. 2004;36 Suppl 1:53-63; Marjamaa A, Ann. Med. 2009;41(3):234-40; Donner BC, Cardiol Young. 2012; 22(3):360-3). Several studies indicate that carriers of this variant have moderately prolonged QT intervals on average (Fodstad H, Ann. Med. 2006; 38(4):294-304; Marjamaa A et al. Ann. Med., 2009;41:234-40; Koponen M et al. BMC Med Genet, 2018 04;19:56). However, this alteration has also been identified in apparently healthy individuals (Ackerman MJ et al. Mayo Clin. Proc. 2003;78:1479-87; Fodstad H, Ann. Med. 2006; 38(4):294-304; Maltese PE et al. Int Heart J. 2017;58(1):81-87). Two functional studies suggest this alteration has an impact on protein function (Fodstad H, Ann. Med. 2006 ; 38(4):294-304; Lahti AL, Dis Model Mech 2012 Mar; 5(2):220-30). Other studies do not detect a significant impact on protein function (Männikkö R et al. Br J Pharmacol, 2010 Jan;159:102-14; Jou CJ et al. Circ. Res. 2013;112:826-30; Soh MS et al. Ann Clin Transl Neurol, 2021 07;8:1422-1432). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.81

MutPred

0.81

Loss of disorder (P = 0.0014);

MVP

0.98

MPC

1.9

ClinPred

0.16

GERP RS

0.76

Varity_R

0.067

gMVP

0.54

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