ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2579G>C (p.Arg860Pro) (rs730880056)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000588534 SCV000697545 uncertain significance not provided 2016-03-07 criteria provided, single submitter clinical testing Variant summary: CACNA1C c.2579G>C affects a conserved nucleotide, resulting in amino acid change from Arg to Pro. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). Another variant at this codon c.2579G>A (p.Arg860Gln) is classified as likely pathogenic in ClinVar and has been reported in the literature. However, the variant of interest has not been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. Additionally, this variant was not found in 116972 control chromosomes. One clinical lab via ClinVar classified this variant as VUS, without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000678964 SCV000805180 likely pathogenic Timothy syndrome 2018-05-18 criteria provided, single submitter clinical testing
Invitae RCV000157123 SCV001384539 uncertain significance Long QT syndrome 2019-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 860 of the CACNA1C protein (p.Arg860Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 180284). 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"). This variant disrupts the p.Arg860 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1C-related conditions (PMID: 25633834, 28600387), which suggests that this may be a clinically significant amino acid residue. 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.
Blueprint Genetics RCV000157123 SCV000206846 uncertain significance Long QT syndrome 2014-08-04 no assertion criteria provided clinical testing

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