ClinVar Miner

Submissions for variant NM_000890.5(KCNJ5):c.554G>T (p.Cys185Phe)

gnomAD frequency: 0.00004  dbSNP: rs760375676
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000693667 SCV000821545 uncertain significance Long QT syndrome 2020-11-15 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KCNJ5-related disease. This variant is present in population databases (rs760375676, ExAC 0.001%). This sequence change replaces cysteine with phenylalanine at codon 185 of the KCNJ5 protein (p.Cys185Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine.
GeneDx RCV001756191 SCV001988182 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Reported as a variant of uncertain significance in ClinVar but additional evidence is not available (ref; ClinVar SCV000821545.1; Landrum et al., 2016)
Ambry Genetics RCV002343476 SCV002651758 uncertain significance Cardiovascular phenotype 2022-05-02 criteria provided, single submitter clinical testing The p.C185F variant (also known as c.554G>T), located in coding exon 1 of the KCNJ5 gene, results from a G to T substitution at nucleotide position 554. The cysteine at codon 185 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available 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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