ClinVar Genomic variation as it relates to human health

Reported in an individual with LQTS (Napolitano et al., 2005) and in an individual with sudden unexplained death while exercising (Farrugia et al., 2015); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 67497; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32048431, 22581653, 26164358, 16414944, 19862833)

This missense variant replaces histidine with tyrosine at codon 1153 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 with cell culture system has shown that this variant causes a reduction in the channel current density, without apparent impact on channel trafficking to the cell membrane (PMID: 34502138). This variant has been reported in an individual affected with long QT syndrome (PMID: 16414944) and in an individual affected with sudden death (PMID: 26164358). This variant has been identified in 10/207056 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 histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1153 of the KCNH2 protein (p.His1153Tyr). This variant is present in population databases (rs199473035, gnomAD 0.009%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16414944, 26164358, 34502138). ClinVar contains an entry for this variant (Variation ID: 67497). 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: 34502138). 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.

This missense variant replaces histidine with tyrosine at codon 1153 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 with cell culture system has shown that this variant causes a reduction in the channel current density, without apparent impact on channel trafficking to the cell membrane (PMID: 34502138). This variant has been reported in an individual affected with long QT syndrome (PMID: 16414944) and in an individual affected with sudden death (PMID: 26164358). This variant has been identified in 10/207056 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.

The p.H1153Y variant (also known as c.3457C>T), located in coding exon 15 of the KCNH2 gene, results from a C to T substitution at nucleotide position 3457. The histidine at codon 1153 is replaced by tyrosine, an amino acid with similar properties. This alteration has been reported in long QT syndrome genetic testing cohorts (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Walsh R et al. Genet Med, 2021 Jan;23:47-58). Additionally, this alteration was detected in a sudden unexplained death cohort, and an in vitro assay showed it may impact protein function (Farrugia A et al. Forensic Sci. Int., 2015 Sep;254:5-11; Farrugia A et al. Int J Mol Sci, 2021 Aug;22:[ePub ahead of print]). 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.

The c.3457 C>T p.(His1153Tyr) variant detected in heterozygosity in the KCNH2 gene, is described in the literature in one patient with Long QT syndrome (PMID: 16414944) and in a case of sudden death (PMID: 26164358). This variant has been identified in population databases dbSNP (rs199473035), gnomAD with allele frequency (AF) of 0.00483%, exome aggregation consortium (ExAC) with AF of 0.00019 and absent in the database ESP. This rare variant is located in a moderately conserved residue in the distal C-terminus domain of the KCNH2 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function (ClinVar ). Bioinformatics tools do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Therefore, it has been classified as a variant of uncertain clinical significance in ClinVar (Variation ID: 67497). Additionally, this variant was described in a German doctoral thesis in a male patient with atypical atrial flutter alternating with typical atrial flutter and paroxysmal atrial fibrillation. The functional characterization of the H1153Y channel variant in Xenopus oocytes showed a loss of function and no dominant negative effect on wild-type (WT) channels (Limberg, M., 2011). These results concur with a recent study that identified this H1153Y KCNH2 variant in a sudden arrhythmic death syndrome case. The study showed that the H1153Y variant causes a loss of KCNH2 channel function that reduces the current density leading to LQT2. (Farrugia, A. et al., 2021).

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Variant interpretted as Uncertain significance and reported on 10-10-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.