ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.476G>A (p.Arg159His)

gnomAD frequency: 0.00001  dbSNP: rs1016201425
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001927043 SCV002206462 uncertain significance Long QT syndrome 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 159 of the KCNH2 protein (p.Arg159His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV003355661 SCV004055131 uncertain significance Cardiovascular phenotype 2023-07-13 criteria provided, single submitter clinical testing The p.R159H variant (also known as c.476G>A), located in coding exon 4 of the KCNH2 gene, results from a G to A substitution at nucleotide position 476. The arginine at codon 159 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is 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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