ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1600C>A (p.Arg534Ser) (rs199472916)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182023 SCV000234326 likely pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing The c.1600 C>A (R534S) likely pathogenic variant in the KCNH2 gene has not been published to our knowledge but has been observed in other individuals with LQTS referred for genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). This variant is located in exon 7 of the KCNH2 gene and may be functionally significant at the mRNA and/or protein level. At the mRNA level, multiple in silico splice prediction algorithms predict that c.1600 C>A may create a cryptic splice donor site upstream of the natural splice donor site of intron 7 which may affect gene splicing. Though, in the absence of functional mRNA studies, the physiological consequence of this variant on splicing cannot be precisely determined. At the protein level, c.1600 C>A encodes the R534S semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore, R534S occurs within the helical transmembrane voltage-sensor S4 domain, and other missense variants at the same residue (R534C, R534L) and nearby residues (R528P, R531W, R531Q, V535M, R537W) have also been reported in HGMD association with LQTS (Stenson et al., 2014), supporting the functional importance of this residue and region of the protein.
Invitae RCV000473348 SCV000543455 uncertain significance Long QT syndrome 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 534 of the KCNH2 protein (p.Arg534Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200728). 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, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg534Cys) is reported to be deleterious (PMID: 9600240, 10690305, 16432067). This suggests that the p.Arg534 residue is important for KCNH2 protein function. In summary, this is a rare missense variant that is predicted to be deleterious and affects a residue important for protein function. However, in the absence of confirmed segregation or functional studies, at this time this change has been classified as a Variant of Uncertain Significance.

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