ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1886A>G (p.Asn629Ser) (rs199472957)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181823 SCV000234126 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing The N629S pathogenic variant in the KCNH2 gene has previously been reported in association with LQTS (Satler et al., 1998; Larsen et al., 2001; Kapplinger et al., 2009; Zhang et al., 2008; Moss et al., 2002; Goldenberg et al., 2011; Christiansen et al., 2014; Riuro et al., 2014). In addition, different pathogenic missense variants affecting the same codon (N629T, N629I) have also been reported in association with LQTS (Chung et al., 2007; Kapplinger et al., 2009; Giudicessi et al., 2012). The N629S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although N629S is a conservative amino acid substitution, it occurs within the selectivity filter motif of the pore region at a position that is conserved across species. Functional studies report N629S affects protein-trafficking causing a dominant-negative effect on the normal protein complex, resulting in loss of normal ion channel function (Anderson et al., 2006). Finally, pathogenic/likely pathogenic variants in nearby residues (N633S, N633I, T634I, T634S) have been reported in HGMD in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678941 SCV000805154 pathogenic Long QT syndrome 2 2018-03-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763171 SCV000893760 pathogenic Short QT syndrome 1; Long QT syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781486 SCV000919553 pathogenic Long QT syndrome 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.1886A>G (p.Asn629Ser) variant involves the alteration of a conserved nucleotide located in the Ion transport domain (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 277188 control chromosomes. Multiple publications cite the variant in affected individuals (Koponen_2015. Moss_2002, Larsen_2001, Satler_1998, Gao_2016). Functional studies report the variant to result in abnormal trafficking (Anderson_2006), and diminished repolarization (Jou_2013). Additionally, other variants at the same codon position (N629D, N629K, N629I, N629T) have also been reported in affected individuals, supporting a functional role of the position. One clinical diagnostic laboratories/reputable database has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000781486 SCV000964701 pathogenic Long QT syndrome 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 629 of the KCNH2 protein (p.Asn629Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in a family (PMID: 9544837) and observed in several individuals affected with this disease (PMID: 18808722, 26063740, 11854117, 24606995, Invitae). This variant is also known as A2069G (N629S) in the literature. ClinVar contains an entry for this variant (Variation ID: 67315). Experimental studies have shown that this missense change results in a trafficking-deficient phenotype and decreased repolarization rescue (PMID: 16432067, 23303164, 25417810). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Asn629 amino acid residue in KCNH2 have been observed in affected individuals (PMID: 17905336, 22573844, 10973849, 16432067, 19841300, 25417810). This suggests that it is a clinically significant residue, and that other 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 RCV000058034 SCV000089554 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:9544837;PMID:11468227;PMID:11668638;PMID:11854117;PMID:16432067;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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