ClinVar Miner

Submissions for variant NM_004982.4(KCNJ8):c.676C>T (p.Arg226Cys)

gnomAD frequency: 0.00001  dbSNP: rs763650307
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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 RCV001875650 SCV002154681 uncertain significance Brugada syndrome 2021-12-03 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ8 protein function. This variant has not been reported in the literature in individuals affected with KCNJ8-related conditions. This variant is present in population databases (rs763650307, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 226 of the KCNJ8 protein (p.Arg226Cys).
Ambry Genetics RCV002361169 SCV002663714 uncertain significance Cardiovascular phenotype 2019-04-18 criteria provided, single submitter clinical testing The p.R226C variant (also known as c.676C>T), located in coding exon 2 of the KCNJ8 gene, results from a C to T substitution at nucleotide position 676. The arginine at codon 226 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species; however, cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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