Submissions for variant NM_000238.4(KCNH2):c.1935G>A (p.Met645Ile)

dbSNP: rs199472973

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431767	SCV000515912	uncertain significance	not provided	2018-10-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNH2 gene. The M645I variant hasbeen previously reported in association with LQTS (Kapplinger et al., 2009; Issa et al., 2015). TheM645I variant was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. This substitution occurs at a position that is conserved across species, andin silico analysis predicts this variant is probably damaging to the protein structure/function. Missensevariants in the same residue (M645V, M645L, M645R) and in nearby residues (F640V, F640L, S641F,V644L, G648S, S649P) have been reported in the Human Gene Mutation Database in association withLQTS (Stenson et al., 2014). Nevertheless, the M645I variant is a conservative amino acidsubstitution, which is not likely to impact secondary protein structure as these residues share similarproperties. Thus, this variant lacks observation in a significant number of affected individuals,segregation data, and functional evidence, which would further clarify its pathogenicity.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058062	SCV000089582	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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.