ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1979C>T (p.Ser660Leu) (rs199472979)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181833 SCV000234136 likely pathogenic not provided 2018-07-18 criteria provided, single submitter clinical testing The S660L variant in the KCNH2 gene has been reported in at least one individual with Romano-Ward syndrome and multiple individuals referred for LQTS genetic testing (Napolitano et al., 2005; Kapplinger et al., 2009). Additionally, this variant has segregated with disease in five additional relatives from two families with LQTS (C. Napolitano, pers. comm., August 12, 2016). It has also been seen in multiple individuals who had genetic testing for LQTS at GeneDx and was found to have occurred de novo in one individual. The S660L variant is not observed in large population cohorts (Lek et al., 2016). Moreover, S660L results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved across species. Functional studies did not identify a trafficking defect when S660L mutant Kv11.1 was co-expressed with wild type channel in HEK293 cells (Anderson et al., 2014). However, the biophysical properties of the mutant channels were not investigated.
Invitae RCV000468503 SCV000543477 uncertain significance Long QT syndrome 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 660 of the KCNH2 protein (p.Ser660Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (rs199472979, ExAC no frequency). This variant has been observed in individuals suspected to have long QT syndrome and several individuals referred for long QT syndrome genetic testing (PMID: 16414944, 19716085, Invitae). ClinVar contains an entry for this variant (Variation ID: 67352). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, experimental studies did not demonstrate a defect in protein trafficking (PMID: 25417810). The clinical significance of this observation is uncertain. 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 RCV000621327 SCV000737497 pathogenic Cardiovascular phenotype 2016-05-18 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,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851290 SCV000993562 likely pathogenic Long QT syndrome 2 2019-06-08 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058072 SCV000089592 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:16414944;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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