NM_000238.4:c.2467C>T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.2467C>T(p.Arg823Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,632 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2467C>T | p.Arg823Trp | missense_variant | Exon 10 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2467C>T | p.Arg823Trp | missense_variant | Exon 10 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1447C>T | p.Arg483Trp | missense_variant | Exon 6 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3300C>T | non_coding_transcript_exon_variant | Exon 8 of 13 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151804Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251454Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151804Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74158
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 823 of the KCNH2 protein (p.Arg823Trp). This variant is present in population databases (rs199473538, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 11854117, 16831322, 19695459, 19716085, 23158531, 23631430). ClinVar contains an entry for this variant (Variation ID: 67402). 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: 11741928, 16432067, 23303164). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: KCNH2 c.2467C>T (p.Arg823Trp) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251454 control chromosomes. c.2467C>T has been reported in the literature in multiple individuals and families affected with Long QT Syndrome (eg. Splawski_2000, Moss_2002, Lieve_2013). These data indicate that the variant is very likely to be associated with disease. In experimental studies, the variant was found to result in deficient trafficking, reduced repolarization, and inability to be rescued by channel blockers (Jou_2013, Anderson_2006, Ficker_2002). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Congenital long QT syndrome Pathogenic:1Other:1
The p.Arg823Trp variant in KCNH2 has been reported in >10 individuals with long QT syndrome (Splawski 2000, Moss 2002, Kapplinger 2009, Nishio 2009, Crotti 2012 , Lieve 2013, Itoh 2016, ClinVar Variation ID 67402) and has also been reported in ClinVar (Variation ID 67402). In vitro functional studies provide some eviden ce that the p.Arg823Trp variant may impact protein function (Ficker 2002, Roti 2 002, Anderson 2006). The p.Arg823Trp variant has also been identified in 1/11170 2 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org/; dbSNP rs199473538). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical signifi cance, the p.Arg823Trp variant is likely pathogenic. -
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:11854117;PMID:16432067;PMID:16831322;PMID:19716085;PMID:11741928). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
not provided Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The p.R823W variant (also known as c.2467C>T), located in coding exon 10 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2467. The arginine at codon 823 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a number of patients with long QT syndrome (Splawski I et al, Circulation 2000 Sep; 102(10):1178-85; Moss AJ et al, Circulation 2002 Feb; 105(7):794-9; Kapplinger JD et al, Heart Rhythm 2009 Sep; 6(9):1297-303; Nishio Y et al, J. Am. Coll. Cardiol. 2009 Aug; 54(9):812-9; Crotti L et al, J. Am. Coll. Cardiol. 2012 Dec; 60(24):2515-24; Itoh H et al, Eur. J. Hum. Genet. 2015 Dec; Izumi G et al, Pediatr Cardiol 2016 Apr). Studies in cultured cell lines and zebrafish embryos suggested this alteration causes protein traffic deficiency that would compromise channel functions (Ficker E et al, J. Biol. Chem. 2002 Feb; 277(7):4989-98; Anderson CL et al, Circulation 2006 Jan; 113(3):365-73; Jou CJ et al, Circ. Res. 2013 Mar; 112(5):826-30). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at