Submissions for variant NM_172056.2(KCNH2):c.1933A>G (p.Met645Val) (rs199472974)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181830	SCV000234133	pathogenic	not provided	2013-11-22	criteria provided, single submitter	clinical testing	p.Met645Val (ATG>GTG): c.1933 A>G in exon 7 of the KCNH2 gene (NM_000238.2). The Met645Val mutation in the KCNH2 gene has been reported as a de novo mutation identified in a neonate with bradycardia, heart failure, ventricular tachycardia, and syncope (Lupoglazoff J et al., 2004). Met645Val was not observed in 200 control alleles (Lupoglazoff J et al., 2004) and it was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations at this residue (Met645Ile, Met645Arg, Met645Leu) and in nearby residues (Val644Leu, Val644Phe, Gly648Ser) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. In summary, Met645Val in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058060	SCV000089580	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:14998624). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.