ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1459G>A (p.Gly487Ser) (rs562875924)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181791 SCV000234094 uncertain significance not provided 2015-08-17 criteria provided, single submitter clinical testing p.Gly487Ser (GGC>AGC): c.1459 G>A in exon 6 of the KCNH2 (aka HERG) gene (NM_000238.2)The Gly487Ser variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly487Ser results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine at a position that is conserved across species. In silico analysis predicts Gly487Ser is probably damaging to the protein structure/function. Mutations in nearby residues (Ile489Phe, Ala490Thr, Ala490Pro, His492Tyr) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Also, the Gly487Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if Gly487Ser is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000462536 SCV000543445 uncertain significance Long QT syndrome 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 487 of the KCNH2 protein (p.Gly487Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs562875924, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with sudden unexpected death, however,  a frameshift variant in a different gene(CACNB2) was also observed in this individual (PMID: 28704380). ClinVar contains an entry for this variant (Variation ID: 200342). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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