ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.4773G>T (p.Lys1591Asn) (rs786205763)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170811 SCV000223366 uncertain significance not provided 2013-11-27 criteria provided, single submitter clinical testing p.Lys1591Asn (AAG>AAT): c.4773 G>T in exon 39 of the CACNA1C gene (NM_000719.6). The K1591N variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The K1591N variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The K1591 residue is conserved across species. In silico analysis predicts K1591N is probably damaging to the protein structure/function. Furthermore, the K1591N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no other disease-causing mutations have been reported in surrounding residues of the CACNA1C protein, indicating this region may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if K1591N is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae RCV000798404 SCV000938021 uncertain significance Long QT syndrome 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1591 of the CACNA1C protein (p.Lys1591Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. 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: 190673). 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: "Deleterious"; PolyPhen-2: "Probably 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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