ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.617_618delinsTT (p.Ser206Ile) (rs1060500660)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459073 SCV000543416 uncertain significance Long QT syndrome 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 206 of the KCNH2 protein (p.Ser206Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 405339). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000599243 SCV000709811 uncertain significance not specified 2018-03-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNH2 gene. The c.617_618delGCinsTT variant has not been published as pathogenic or been reported as benign to our knowledge. However, it has been observed in one other individual referred for LQTS genetic testing at GeneDx, although no segregation data are available. This variant is also not observed in large population cohorts (Lek et al., 2016). The c.617_618delGCinsTT variant results in the deletion of two base pairs, and insertion of two different base pairs, which leads to the replacement of a serine (S) residue with an isoleucine (I) residue at codon position 206, denoted S206I. The S206I 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. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.

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