rs199473433
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBS2_Supporting
The NM_000238.4(KCNH2):c.2680C>T(p.Arg894Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,452,834 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R894H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2680C>T | p.Arg894Cys | missense_variant | 11/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2680C>T | p.Arg894Cys | missense_variant | 11/15 | 1 | NM_000238.4 | P1 | |
KCNH2 | ENST00000330883.9 | c.1660C>T | p.Arg554Cys | missense_variant | 7/11 | 1 | |||
KCNH2 | ENST00000684241.1 | n.3513C>T | non_coding_transcript_exon_variant | 9/13 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000818 AC: 2AN: 244528Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133006
GnomAD4 exome AF: 0.00000482 AC: 7AN: 1452834Hom.: 0 Cov.: 37 AF XY: 0.00000415 AC XY: 3AN XY: 723174
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | KCNH2: PM5, PM2:Supporting, PP2, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2018 | The R894C variant of uncertain significance in the KCNH2 gene has been reported in one individual referred for LQTS testing (Kapplinger et al., 2009). Wang et al. (2014) identified R894C in a 38 year-old woman with sudden unexplained death and negative autopsy. The R894C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R894C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, a majority of splice-prediction algorithms predict that R894C creates a new cryptic splice donor site located upstream of natural splice donor site in intron 7; however, the new upstream donor site is predicted to be weaker than natural site. Lastly, a variant at this same residue (R894L) has been reported in HGMD in association with LQTS (Stenson et al., 2014), although the clinical significance of this variant has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2019 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with LQTS (Invitae), LQTS and congenital heart malformations (PMID: 28532774), sudden unexpected death (PMID: 24631775), and in an individual referred for LQTS genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67424). This variant is present in population databases (rs199473433, ExAC 0.002%). This sequence change replaces arginine with cysteine at codon 894 of the KCNH2 protein (p.Arg894Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 27, 2023 | This missense variant replaces arginine with cysteine at codon 894 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with long QT syndrome (PMID: 28532774, ClinVar SCV000935380.5), in an individual suspected of having long QT syndrome (PMID: 19716085), and in an individual affected with sudden unexplained death (PMID: 24631775). This variant has been identified in 2/244528 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2023 | The p.R894C variant (also known as c.2680C>T), located in coding exon 11 of the KCNH2 gene, results from a C to T substitution at nucleotide position 2680. The arginine at codon 894 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in long QT syndrome cohorts and a sudden unexplained death cohort; however clinical details were limited in some cases (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Wang D et al. Forensic Sci Int, 2014 Apr;237:90-9; Ebrahim MA et al. Am J Cardiol, 2017 Jul;120:256-261). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at