ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1660C>T (p.Arg554Cys) (rs199473433)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181880 SCV000234183 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing The R894C variant of uncertain significance in the KCNH2 gene has been reported in one individual referred for LQTS testing (Kapplinger et al., 2009). Wang et al. (2014) identified R894C in a 38 year-old woman with sudden unexplained death and negative autopsy. The R894C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R894C variant is 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, a majority of splice-prediction algorithms predict that R894C creates a new cryptic splice donor site located upstream of natural splice donor site in intron 7; however, the new upstream donor site is predicted to be weaker than natural site. Lastly, a variant at this same residue (R894L) has been reported in HGMD in association with LQTS (Stenson et al., 2014), although the clinical significance of this variant has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000795899 SCV000935380 uncertain significance Long QT syndrome 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 894 of the KCNH2 protein (p.Arg894Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199473433, ExAC 0.002%). This variant has been observed in individuals affected with LQTS (Invitae), LQTS and congenital heart malformations (PMID: 28532774), sudden unexpected death (PMID: 24631775), and in an individual referred for LQTS genetic testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67424). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058149 SCV000089669 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: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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