rs143512106
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000238.4(KCNH2):c.2653C>T(p.Arg885Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0001 in 1,612,162 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.2653C>T | p.Arg885Cys | missense_variant | Exon 11 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.2653C>T | p.Arg885Cys | missense_variant | Exon 11 of 15 | 1 | NM_000238.4 | ENSP00000262186.5 | ||
KCNH2 | ENST00000330883.9 | c.1633C>T | p.Arg545Cys | missense_variant | Exon 7 of 11 | 1 | ENSP00000328531.4 | |||
KCNH2 | ENST00000684241.1 | n.3486C>T | non_coding_transcript_exon_variant | Exon 9 of 13 |
Frequencies
GnomAD3 genomes AF: 0.000106 AC: 16AN: 151578Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000224 AC: 56AN: 249574Hom.: 0 AF XY: 0.000266 AC XY: 36AN XY: 135168
GnomAD4 exome AF: 0.000100 AC: 146AN: 1460584Hom.: 0 Cov.: 37 AF XY: 0.000109 AC XY: 79AN XY: 726744
GnomAD4 genome AF: 0.000106 AC: 16AN: 151578Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10AN XY: 73992
ClinVar
Submissions by phenotype
Long QT syndrome Uncertain:3
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This missense variant replaces arginine with cysteine at codon 885 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). A functional study has shown that this variant does not change the biophysical properties of the protein (PMID: 18222468). This variant has been reported in several individuals affected with or suspected of having long QT syndrome (PMID: 18752142, 19716085, 27920829, 30369311), and in another individual affected with sudden infant death syndrome (PMID: 17210839). One of these individuals also carried a pathogenic splicing variant in the KCNH2 gene that could explain the observed phenotype (PMID: 27920829). This variant has also been identified in 58/280856 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. -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 885 of the KCNH2 protein (p.Arg885Cys). This variant is present in population databases (rs143512106, gnomAD 0.03%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 17210839, 18752142, 19716085, 27920829, 30369311). ClinVar contains an entry for this variant (Variation ID: 67422). 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 does not substantially affect KCNH2 function (PMID: 18222468). 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. -
Congenital long QT syndrome Benign:1Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16244680;PMID:17210839;PMID:18752142;PMID:19716085;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Heterozygous variant NM_000238:c.2653C>T (p.Arg885Cys) in the KCNH2 gene was found on WES data in female proband (13 y.o., Caucasian) with Long QT syndrome. An additional variant NM_003098:c.787G>T (p.Ala263Ser) in the SNTA1 gene was found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0002065 (Date of access 08-08-2023). Clinvar contains entry for this variant (Variation ID: 67422). This variant has been reported in over a dozen studies in patients with variable phenotypes. Experimental data showed the variant exhibited biophysical properties indistinguishable from WT-HERG (PMID: 18752142). Most in silico predictors show pathogenic result of the protein change (varsome.com). In accordance with ACMG(2015) criteria and enhanced rare variant interpretation in inherited arrhythmias (PMID: 32893267) this variant is classified as Benign with following criteria selected: BS1, BS3, PM1, PP2, PP3. -
not specified Uncertain:1
Variant summary: KCNH2 c.2653C>T (p.Arg885Cys) 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 0.0002 in 275594 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), suggesting the variant may be benign. However, this observation must be interpreted cautiously due to the presence of potenially affected individuals in the ExAC and gnomAD databases. c.2653C>T has been reported in the literature in individuals affected with Arrhythmia without strong evidence for or against pathogenicity. However, one publication reported a co-occurrence with a pathogenic KCNH2 variant (c.1557+1G>C), providing supporting evidence for a benign role (Burns_2016). One publication reports experimental evidence suggesting there is no functional effect of the variant, though the data was not presented for review (Rhodes_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional information becomes available. -
Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
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Cardiac arrhythmia Uncertain:1
This missense variant replaces arginine with cysteine at codon 885 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). A functional study has shown that this variant does not change the biophysical properties of the protein (PMID: 18222468). This variant has been reported in several individuals affected with or suspected of having long QT syndrome (PMID: 18752142, 19716085, 27920829, 30369311), and in another individual affected with sudden infant death syndrome (PMID: 17210839). One of these individuals also carried a pathogenic splicing variant in the KCNH2 gene that could explain the observed phenotype (PMID: 27920829). This variant has also been identified in 58/280856 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. -
not provided Benign:1
KCNH2: BP2, BS3:Supporting -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at