Submissions for variant NM_172056.2(KCNH2):c.1886A>C (p.Asn629Thr) (rs199472957)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413164	SCV000490551	pathogenic	not provided	2015-08-10	criteria provided, single submitter	clinical testing	The N629T pathogenic variant in the KCNH2 gene has been reported in one individual of European ancestry who was diagnosed with LQTS at the age of 3 years and had a family history of a first degree relative with sudden death before the age of 35 years (Chung S et al., 2007). N629T results in a conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, pathogenic variants affecting this same residue, (N629S, N629I, N629K, N629D) and nearby residues (G628R, G628A, G628S, G628V, V630A, V630L) in the highly conserved pore region have been reported in the Human Gene Mutation Database in association with LQTS (Stenson P et al., 2014), further supporting the functional importance of this residue and this region of the protein. Furthermore, N629T was not observed in approximately 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. In summary, N629T in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae	RCV000475088	SCV000543415	likely pathogenic	Long QT syndrome	2016-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with threonine at codon 629 of the KCNH2 protein (p.Asn629Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual affected with long QT syndrome (PMID: 17905336). ClinVar contains an entry for this variant (Variation ID: 67314). Other missense substitutions at this codon (p.Asn629Asp, p.Asn629Ser, p.Asn629Ile, p.Asn629Lys) have been determined to be pathogenic (PMID: 10973849, 16432067, 19841300, 25417810). This suggests that the asparagine residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. This variant identified in the KCNH2 gene is located in the pore region of the resulting protein (PMID: 19841300, 25348405). Experimental studies have shown that it alters the properties of the channel (PMID: 22573844). For these reasons, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058033	SCV000089553	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:17905336). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.