ClinVar Genomic variation as it relates to human health

Low GERP score may suggest that this variant may belong in a lower pathogenicity class

Variant summary: KCNH2 c.2660G>A (p.Arg887His) results in a non-conservative amino acid change in 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 8e-06 in 248800 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2660G>A has been reported in the literature in two individuals affected with long QT syndrome (Adler_2016, Tester_2005). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Experimental evidence evaluating an impact on protein function, demonstrated the variant increased the degradation of the protein thus decreasing Kv11.1 channel abundance on the cell surface and consequently measured ion current density was also decreased, however the in vivo effects of this partially reduced expression cannot be clearly predicted from these data (Donovan_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these laboratories classified the variant as likely pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 887 of the KCNH2 protein (p.Arg887His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 15840476, 26743238). ClinVar contains an entry for this variant (Variation ID: 67423). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 22653970). 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.

The p.R887H variant (also known as c.2660G>A), located in coding exon 11 of the KCNH2 gene, results from a G to A substitution at nucleotide position 2660. The arginine at codon 887 is replaced by histidine, an amino acid with highly similar properties. This variant was previously described in a long QT syndrome genetic testing cohort and in a primary electrical syndrome cohort (Tester et al. Heart Rhythm. 2005;2(5):507-17; Adler A et al. Circ Arrhythm Electrophysiol. 2016;9:e003440). In functional in vitro analyses, this variant adversely affected the potassium ion channel by inhibiting surface expression and current density (Donovan AJ et al. Mol Pharmacol. 2012;82(3):428-37). 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.

The R887H likely pathogenic variant in the KCNH2 gene has been reported in one individual referred for LQTS testing and was absent in greater than 1,500 reference alleles (Tester et al., 2005). In functional studies, R887H was shown to disrupt PKC alpha-dependent phosphorylation and ultimately inhibit surface expression and current density (Donovan et al., 2012). The R887H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC). Missense variants in the same residue (R887C) and in nearby residues (R885C, R885H, R894C, R894L) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). Although this substitution occurs at a position that is conserved across species, the R887H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, the R887H variant in the KCNH2 gene is likely pathogenic. However, in order to definitively determine its clinical significance, additional data is required.

This missense variant replaces arginine with histidine at codon 887 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). An experimental study has shown that this variant may inhibit PKC-dependent phosphorylation and ultimately inhibit cell surface expression and function of the potassium channel (PMID: 22653970). This variant has been reported in an individual affected with arrhythmia (PMID 26743238) and in an individual referred for long QT genetic testing (PMID: 15840476). This variant has been identified in 2/248800 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 missense variant replaces arginine with histidine at codon 887 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). An experimental study has shown that this variant may inhibit PKC-dependent phosphorylation and ultimately inhibit cell surface expression and function of the potassium channel (PMID: 22653970). This variant has been reported in an individual affected with arrhythmia (PMID 26743238) and in an individual referred for long QT genetic testing (PMID: 15840476). This variant has been identified in 2/248800 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 variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:17161064;PMID:22378279;PMID:22653970). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.