ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5033A>G (p.Glu1678Gly) (rs786205781)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170847 SCV000223402 uncertain significance not provided 2014-10-28 criteria provided, single submitter clinical testing p.Glu1678Gly (GAG>GGG): c.5033 A>G in exon 41 of the CACNA1C gene (NM_000719.6). The E1678G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E1678G variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1678G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in vertebrates. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in BRUGADA panel(s).
Invitae RCV000631675 SCV000752758 uncertain significance Long QT syndrome 2017-10-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1678 of the CACNA1C protein (p.Glu1678Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190708). 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: "Deleterious"; 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.

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