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 0.000349 in 152020 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity,risk factor (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
Links
ACMG classification
Verdict is Uncertain_significance.
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: 53AN: 152020Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000324 AC: 25AN: 77224Hom.: 0 AF XY: 0.000270 AC XY: 12AN XY: 44402
GnomAD4 exome AF: 0.000324 AC: 426AN: 1314244Hom.: 1 AF XY: 0.000346 AC XY: 224AN XY: 647814
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at