rs36210422

chr7-150958449-G-Achr7-150958449-G-C

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting interpretations of pathogenicity; risk factor criteria provided, conflicting interpretations U:9 B:4 O:3
• Conservation: PhyloP100: 1.14

ACMG classification

Verdict is Uncertain_significance.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• BS2: High AC in GnomAd at 53 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.526C>T	p.Arg176Trp	missense_variant	4/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.526C>T	p.Arg176Trp	missense_variant	4/15	1	NM_000238.4	P1
KCNH2	ENST00000532957.5	n.749C>T		non_coding_transcript_exon_variant	4/9	2
KCNH2	ENST00000684241.1	n.1359C>T		non_coding_transcript_exon_variant	2/13

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152020 Hom.: 0 Cov.: 33

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: 25 AN: 77224 Hom.: 0 AF XY: 0.000270 AC XY: 12 AN XY: 44402

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.: 1 AF XY: 0.000346 AC XY: 224 AN XY: 647814

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

Alfa AF: 0.000530 Hom.: 0

Bravo AF: 0.000215

ExAC AF: 0.000171 AC: 7

ClinVar

Significance: Conflicting interpretations of pathogenicity; risk factor

Submissions summary: Uncertain:9Benign:4Other:3

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

Long QT syndrome 2 Uncertain:2Benign:1Other:1

risk factor, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Nov 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2022	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). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n=7, likely benign, n=2, risk factor, n=1). Based on the evidence outlined above, the variant in isolation was classified as likely benign. -

not provided Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	Criteria applied: PP2, PP3, BS2 -
not provided, no assertion provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2023	Reported in association with LQTS but also present in asymptomatic individuals, control individuals, and individuals who also harbor additional cardiogenetic variants referred for genetic testing at GeneDx or in published literature (Swan H et al., 1999; Laitinen P et al., 2000; Ackerman MJ et al., 2003; Mank-Seymour AR et al., 2006; Fodstad H et al., 2006; Donner BC et al., 2012; Stattin EL et al., 2012; Christiansen M et al., 2014; Koponen M et al., 2015; Maltese PE et al., 2017); 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 (Fodstad H et al., 2006; Lathi AL et al., 2012; Jou CJ et al., 2013; Soh MS et al., 2021); 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, 36269083, 36860515, 36597672) -

Long QT syndrome Uncertain:1Benign:1Other:1

Uncertain significance, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jul 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2022	- -
risk factor, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Short QT syndrome type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 21, 2019

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

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 08, 2022

ACMG categories: PM2,PP3 -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

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, the in silico prediction for this alteration is inconclusive. 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

CardioboostArm

Benign

0.014

BayesDel_addAF

Uncertain

0.059

T

BayesDel_noAF

Pathogenic

0.23

Cadd

Uncertain

24

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.52

D

LIST_S2

Uncertain

0.89

D

M_CAP

Pathogenic

0.68

D

MetaRNN

Pathogenic

0.96

D

MetaSVM

Pathogenic

0.83

D

MutationAssessor

Benign

1.7

L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.85

D

PROVEAN

Uncertain

-2.8

D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

D

Sift4G

Uncertain

0.014

D

Polyphen

1.0

D

Vest4

0.81

MutPred

0.81

Loss of disorder (P = 0.0014);

MVP

0.98

MPC

1.9

ClinPred

0.16

T

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

Other links and lift over

dbSNP: rs36210422; hg19: chr7-150655537;