ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2200C>T (p.Arg734Cys) (rs143072395)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182043 SCV000234346 uncertain significance not provided 2018-10-15 criteria provided, single submitter clinical testing The Arg734Cys (R734C) variant of uncertain significance in the KCNH2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been identified independently in two individuals referred for LQTS genetic testing at GeneDx, however, segregation data is limited or absent due to the lack of clinical information provided and/or insufficient participation by informative family members. R734C is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R734C 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. Moreover, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Although several missense variants in nearby residues (I728N, H731P, L732P, S735L), have been reported in the Human Gene Mutation Database as likely associated with LQTS (Stenson et al., 2014), the pathogenicity of each of these variants has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

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