ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.736G>T (p.Gly246Cys)

gnomAD frequency: 0.00001  dbSNP: rs1057520689
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000433548 SCV000516994 likely benign not specified 2015-05-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001851049 SCV002256131 uncertain significance Long QT syndrome 2023-01-28 criteria provided, single submitter clinical testing The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. 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. ClinVar contains an entry for this variant (Variation ID: 379687). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 246 of the KCNH2 protein (p.Gly246Cys).
Ambry Genetics RCV002379315 SCV002672084 uncertain significance Cardiovascular phenotype 2022-07-01 criteria provided, single submitter clinical testing The p.G246C variant (also known as c.736G>T), located in coding exon 4 of the KCNH2 gene, results from a G to T substitution at nucleotide position 736. The glycine at codon 246 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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