Submissions for variant NM_000238.4(KCNH2):c.1826A>G (p.Asp609Gly)

dbSNP: rs199472940

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001211004	SCV001382525	uncertain significance	Long QT syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 609 of the KCNH2 protein (p.Asp609Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome and arrhythmogenic cardiomyopathy (PMID: 15500450, 30844837). ClinVar contains an entry for this variant (Variation ID: 67289). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 15500450, 25417810). This variant disrupts the p.Asp609 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 11222472, 11854117, 18808722, 25417810, 26669661). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV002408564	SCV002715561	pathogenic	Cardiovascular phenotype	2018-03-07	criteria provided, single submitter	clinical testing	The p.D609G pathogenic mutation (also known as c.1826A>G), located in coding exon 7 of the KCNH2 gene, results from an A to G substitution at nucleotide position 1826. The aspartic acid at codon 609 is replaced by glycine, an amino acid with similar properties, and is located in the S5/pore transmembrane spanning region. This alteration was determined to be the result of a de novo mutation in one individual with a severely prolonged QT interval who was also heterozygous for an alteration in KCNQ1 (Yamaguchi M et al. Clin. Sci. 2005;108:143-50). In addition, in a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Functional studies indicate that this variant has deficient protein function (Yamaguchi M et al. Clin. Sci. 2005;108:143-50; Anderson CL et al. Nat Commun. 2014;5:5535). Furthermore, a likely pathogenic alteration affecting the same codon, p.D609N, has also been reported in association with LQTS (Westenskow P et al. Circulation. 2004;109:1834-41). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058005	SCV000089525	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:15500450;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.