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rs36210422

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

6
7
7

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]

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ACMG classification

Classification made for transcript

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
KCNH2NM_000238.4 linkuse as main transcriptc.526C>T p.Arg176Trp missense_variant 4/15 ENST00000262186.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.526C>T p.Arg176Trp missense_variant 4/151 NM_000238.4 P1Q12809-1
KCNH2ENST00000532957.5 linkuse as main transcriptn.749C>T non_coding_transcript_exon_variant 4/92
KCNH2ENST00000684241.1 linkuse as main transcriptn.1359C>T non_coding_transcript_exon_variant 2/13

Frequencies

GnomAD3 genomes
AF:
0.000349
AC:
53
AN:
152020
Hom.:
0
Cov.:
33
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:
25
AN:
77224
Hom.:
0
AF XY:
0.000270
AC XY:
12
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.:
1
Cov.:
32
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:
53
AN:
152128
Hom.:
0
Cov.:
33
AF XY:
0.000282
AC XY:
21
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.:
0
Bravo
AF:
0.000215
ExAC
AF:
0.000171
AC:
7

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
Uncertain significance, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMay 31, 2022- -
risk factor, flagged submissionclinical testingBlueprint GeneticsSep 24, 2015- -
Uncertain significance, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 09, 2018The 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. -
Likely benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
not specified Uncertain:2Benign:1
Uncertain significance, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalNov 10, 2015- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 03, 2017Variant 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 31, 2023Variant 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. -
Long QT syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterresearchDept of Medical Biology, Uskudar UniversityJan 08, 2024Criteria: BS1, PP2, PP3 -
Uncertain significance, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteNov 10, 2022Risk factor for disease development: PS4; PP1_strong; PS3_mod; PP2; PP3; BS1; BS2 -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
not provided Uncertain:1Benign:1Other:1
not provided, no classification providedliterature onlyCardiovascular 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). -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024KCNH2: PP2, PP3, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 30, 2023Reported 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) -
Short QT syndrome type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJan 21, 2019This 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 submitterclinical testingInstitute of Human Genetics, University Hospital MuensterApr 08, 2022ACMG categories: PM2,PP3 -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 30, 2023The 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
Benign
23
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs36210422; hg19: chr7-150655537; API