ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.6011G>T (p.Gly2004Val) (rs374991642)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546112 SCV000627581 uncertain significance Long QT syndrome 2018-07-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2004 of the CACNA1C protein (p.Gly2004Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs374991642, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 456989). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000618390 SCV000737650 uncertain significance Cardiovascular phenotype 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000763839 SCV000894761 uncertain significance Timothy syndrome; Brugada syndrome 3 2018-10-31 criteria provided, single submitter clinical testing

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