Submissions for variant NM_172056.2(KCNH2):c.1825G>A (p.Asp609Asn) (rs199472941)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413200	SCV000490902	pathogenic	not provided	2016-05-31	criteria provided, single submitter	clinical testing	The D609N pathogenic variant in the KCNH2 gene has been reported in association with LQTS(Splawski et al., 2000; Lupoglazoff et al., 2001; Moss et al., 2002; Westenskow et al., 2004; Zhang etal., 2008). In addition, functional studies show that the D609N variant does result in deficient proteintrafficking (Anderson et al., 2014). The D609N variant results in a semi-conservative amino acidsubstitution at a position that is conserved across species. Variants in the same residue (D609H,D609Y, D609G) and in nearby residues (G604S, T613A, T613M) have been reported in HGMD inassociation with LQTS (Stenson et al., 2014), further supporting the functional importance of thisregion of the protein. Furthermore, the D609N pathogenic variant was not observed in approximately6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. Therefore, we interpret the D609N variant as pathogenic.
Invitae	RCV000526585	SCV000627439	pathogenic	Long QT syndrome	2019-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 609 of the KCNH2 protein (p.Asp609Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 10973849, 11854117, 11222472, 18808722, 26669661). ClinVar contains an entry for this variant (Variation ID: 67286). This variant has been reported to affect KCNH2 protein function (PMID: 25417810). This variant disrupts the p.Asp609 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with individuals with KCNH2-related conditions (PMID: 15500450, 25417810), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058002	SCV000089522	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:10973849;PMID:11222472;PMID:11854117;PMID:15051636). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.