ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1898A>G (p.Asn633Ser) (rs199472961)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181825 SCV000234128 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The N633S pathogenic variant in the KCNH2 gene has been reported in multiple individuals in association with LQTS (Satler et al., 1998; Lupoglazoff et al., 2001; Tester et al., 2005; Nagaoka et al., 2008; Itoh et al., 2016; Izumi et al., 2016). It has also been observed in several individuals referred for arrhythmia genetic testing at GeneDx, and at least two de novo occurrences were identified through parental testing, although identity studies were not performed. Additionally, this variant has been shown to segregate with LQTS in at least three affected relatives from unrelated families, as reported by Satler et al. (1998) and observed at GeneDx. This variant is also not observed in large population cohorts (Lek et al., 2016). Although N633S is a conservative amino acid substitution, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, this variant occurs adjacent to the pore loop in the S5-S6 linker region, and functional studies suggest that N633S impairs proper KCNH2 channel trafficking and channel function (She et al., 2006; Anderson et al., 2014). Finally, other missense variants at the same residue (N633I, N633D, N633K) and in nearby residues (G628S, N629S, N629T, N629I, T634I, N635S) have been reported at GeneDx and/or in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein.In summary, N633S in the KCNH2 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000617489 SCV000736310 likely pathogenic Cardiovascular phenotype 2016-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678919 SCV000805125 pathogenic Long QT syndrome 2 2017-11-27 criteria provided, single submitter clinical testing
Invitae RCV000799027 SCV000938674 pathogenic Long QT syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 633 of the KCNH2 protein (p.Asn633Ser). 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 in several individuals affected with long QT syndrome (LQTS) (PMID: 9544837, 22949429, 17088455, 19996378). ClinVar contains an entry for this variant (Variation ID: 67323). This variant has been reported to affect KCNH2 protein function (PMID: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. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058042 SCV000089562 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:11222472;PMID:12877697;PMID:15840476;PMID:16842670;PMID:18441445;PMID:18752142;PMID:19841300). 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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