Submissions for variant NM_000238.4(KCNH2):c.1750G>T (p.Gly584Cys)

dbSNP: rs199473428

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181817	SCV000234120	pathogenic	not provided	2013-01-07	criteria provided, single submitter	clinical testing	p.Gly584Cys (GGC>TGC): c.1750 G>T in exon 7 of the KCNH2 (aka HERG) gene (NM_000238.2)The Gly584Cys mutation in the KCNH2 gene has been reported in at least one Japanese family with LQTS and it was absent from 200 Japanese control individuals (Nagaoka I et al., 2008; Itoh H et al., 2010). Gly584Cys results in a non-conservative amino acid substitution of a non-polar Glycine with a neutral, polar Cysteine at a residue that is conserved across species. In addition, Gly584Cys is located in the S5-pore transmembrane domain, where other missense mutations at the same codon (Gly584Ser, Gly584Val) and nearby codons (Ile583Val, Trp585Cys) have also been reported in association with LQTS. The NHLBI ESP Exome Variant Server reports Gly584Cys was not observed in approximatly 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common variant in these populations.In summary, Gly584Cys in the KCNH2 is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820068	SCV000960762	uncertain significance	Long QT syndrome	2018-10-14	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 584 of the KCNH2 protein (p.Gly584Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gly584 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 19490267, 10862094, 10973849, 17222736, 22949429, 24606995), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change is well tolerated in free thiol state, but further modifications produce a significant impact on channel function (PMID: 12407082). This variant has been observed in an individual affected with long QT syndrome (PMID: 18441445). ClinVar contains an entry for this variant (Variation ID: 67263).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057976	SCV000089496	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:18441445). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.