ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Identified in a Japanese patient with sudden infant death syndrome who also harbored a variant in the SCN5A gene (Otagiri et al., 2008); Identified in a Japanese man, his father, and his son, all of whom were affected with persistent or paroxysmal palpitations; the proband's ECG showed a normal QTc interval (Hayashi et al., 2015); Published functional studies suggested a gain-of-function effect (Otagiri et al., 2008; Hayashi et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31043699, 18596570, 26129877, 22581653, 26332594, 22995991)

The c.2684C>T;p.(Thr895Met) missense change has been observed in affected individual(s)(PMID: 26129877; 18596570; 23304551; 21215473; 20674198) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 26129877; 18596570) - PS3_supporting. The variant is present at low allele frequencies population databases (rs199473434– gnomAD 0.0005351%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic

This missense variant replaces threonine with methionine at codon 895 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). In vitro functional studies have shown that this variant may affect the amplitude of current and causes a delay in deactivation of the potassium channels (PMID: 18596570, 26129877). This variant has been reported in an individual affected with atrial fibrillation, as well as in the proband's father and son affected with paroxysmal palpitations (PMID: 26129877). This variant has also been reported in an infant affected with sudden death syndrome (PMID: 18596570), and in two individuals suspected of having epilepsy (PMID: 31696929). This variant has also been identified in 6/273882 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 895 of the KCNH2 protein (p.Thr895Met). This variant is present in population databases (rs199473434, gnomAD 0.01%). This missense change has been observed in individual(s) with atrial fibrillation and in two relatives with paroxysmal palpitations (PMID: 18596570, 26129877). ClinVar contains an entry for this variant (Variation ID: 67426). 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: 18596570, 26129877). 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 threonine with methionine at codon 895 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An electrophysiological study in cell culture has shown that this variant may affect the deactivation time course of the potassium channels (PMID: 26129877). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with atrial fibrillation, as well as in the proband's father and son affected with paroxysmal palpitations (PMID: 26129877). This variant has been reported in an infant affected with sudden death syndrome (PMID: 18596570). This variant has also been identified in 6/273882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 c.2684C>T (p.T895M) alteration is located in exon 11 (coding exon 11) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2684, causing the threonine (T) at amino acid position 895 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:18596570). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.