Submissions for variant NM_172057.2(KCNH2):c.1438G>A (p.Gly480Arg) (rs199473001)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429479	SCV000515843	pathogenic	not provided	2015-03-19	criteria provided, single submitter	clinical testing	The G820R variant in the KCNH2 gene has been reported in at least two unrelated individuals withLQTS and was absent in <1,300 healthy control individuals (Tester D et al., 2005; Giudicessi J et al.,2012). In addition, G820R was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. G820R results in a non-conservative amino acid substitution at aposition that is conserved in mammalian species. Consequently, In silico analysis predicts this variant isprobably damaging to the protein structure/function. Furthermore, a variant in the same residue (G820E)and in nearby residues (S818L, S818P, V822M, R823W) have been reported in the HumanGene Mutation Database in association with LQTS (Stenson P et al., 2014), further supporting thefunctional importance of this residue and region of the protein. In summary, G820R in the KCH2 gene is interpreted as a pathogenic variant.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058124	SCV000089644	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.