ClinVar Genomic variation as it relates to human health

p.Phe805Cys (TTT>TGT): c.2414 T>G in exon 10 of the KCNH2 gene (NM_000238.2)The Phe805Cys mutation in the KCNH2 gene has been reported previously in one individual diagnosed with LQTS (Splawski I et al., 2000). Functional studies have shown that Phe805Cys results in a trafficking defect and consequent reduced potassium channel current (Ficker E et al., 2002; Anderson C et al., 2006). Also, a mutation affecting this same residue, Phe805Ser, has been reported in association with LQTS and was absent from more than 400 control alleles in this study (Splawski I et al., 2000). Mutations in nearby residues (Gly800Glu, Gly800Trp, Gly806Glu) have been reported in association with LQTS, supporting the functional importance of this residue and this region of the protein. Furthermore, Phe805Cys was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Phe805Cys in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).

For these reasons, this variant has been classified as Likely Pathogenic. This variant identified in the KCNH2 gene is located in the cytoplasmic cyclic nucleotide binding region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. Experimental studies have shown that this variant affects protein trafficking and therefore potassium channel current (PMID: 16432067, 23303164, 11741928, 12837749) This variant has been reported in a family affected with long QT syndrome (PMID: 11854117). ClinVar contains an entry for this variant (Variation ID: 67397). This variant is not present in population databases (rs199472999, ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 805 of the KCNH2 protein (p.Phe805Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine.

The p.F805C variant (also known as c.2414T>G), located in coding exon 10 of the KCNH2 gene, results from a T to G substitution at nucleotide position 2414. The phenylalanine at codon 805 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the cyclic nucleotide binding domain. This alteration has been previously reported in long QT syndrome cohorts; however, clinical details were limited (Splawski I et al. Circulation. 2000;102:1178-85; Tester DJ et al. Heart Rhythm. 2005;2:507-17). In vitro analyses performed in human cell lines by multiple labs demonstrate that F805C results in defective trafficking and reduced potassium current (Ficker E et al. J. Biol. Chem. 2002;277:4989-98; Delisle BP et al. J. Biol. Chem. 2003;278:35749-54; Walker VE et al. J. Biol. Chem. 2007;282:23509-16). A functional assay in zebrafish also suggests that this variant results in deficient protein function (Jou CJ et al. Circ. Res. 2013;112:826-30). Internal structural analysis indicates that the alteration lies buried in a domain and is more destabilizing than other variants in the region; however, the only other buried variant in the region is stabilizing (Wang W and McKinnon R. Cell. 2017;169(3):422-430). 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.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18468596;PMID:11741928). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.