ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.563C>T (p.Ala188Val) (rs794728356)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181762 SCV000234065 uncertain significance not provided 2013-03-20 criteria provided, single submitter clinical testing p.Ala188Val (GCG>GTG): c.563 C>T in exon 4 of the KCNH2 (aka HERG) gene (NM_000238.2). The Ala188Val variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala188Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is not well conserved across species. In silico analysis predicts Ala188Val is benign to the protein structure/function. Nevertheless, the Ala188Val variant was not observed in approximately 3,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Also, a mutation in a nearby codon (Arg176Trp) has been reported in association with LQTS, supporting the functional importance of this region of the protein. With the clinical and molecular information available at this time, we cannot definitively determine if Ala188Val is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000475233 SCV000543458 uncertain significance Long QT syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 188 of the KCNH2 protein (p.Ala188Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. While this variant is not present in population databases (rs794728356), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a KCNH2-related disease. This variant identified in the KCNH2 gene is located in the cytoplasmic PAC region of the resulting protein (PMID: 19841300), but it is unclear how this variant impacts the function of this protein. ClinVar contains an entry for this variant (Variation ID: 200293). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect 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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