ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.983G>A (p.Arg328His) (rs747437736)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181775 SCV000234078 uncertain significance not provided 2013-06-26 criteria provided, single submitter clinical testing p.Arg328His (CGC>CAC): c.983 G>A in exon 5 of the KCNH2 gene (NM_000238.2). The Arg328His variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg328His results in a conservative amino acid substitution of one positively-charged amino acid for another, this substitution occurs at a position that is conserved across most species. Mutations in nearby residues (Ser320Leu, Asp323Asn, Pro334Leu) have been reported in association with LQTS, further supporting the functional significance of this region of the protein. In silico algorithms are not consistent in their predictions but at least two concur that Arg328His is benign to the protein structure/function. A more severe amino acid substitution at this same residue, Arg328Cys, has been reported in two individuals referred for LQTS testing (Tester D et al., 2005), however in vitro functional studies of Arg328Cys showed that this variant had no effect on current density (Grunnet M et al., 2005). Nevertheless, neither Arg328His nor Arg328Cys were observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating they are not common benign variants in these populations. With the clinical and molecular information available at this time, we cannot definitively determine if Arg328His is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000470774 SCV000543443 uncertain significance Long QT syndrome 2016-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 328 of the KCNH2 protein (p.Arg328His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs747437736, ExAC 0.03%) but has not been reported in the literature in individuals with a KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200315). 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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