ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5098G>A (p.Gly1700Ser) (rs761966966)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631551 SCV000752633 uncertain significance Long QT syndrome 2019-05-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1700 of the CACNA1C protein (p.Gly1700Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs761966966, ExAC 0.06%). This variant has not been reported in the literature in individuals with CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 526905). 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"). 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.
Fulgent Genetics,Fulgent Genetics RCV000763835 SCV000894757 uncertain significance Timothy syndrome; Brugada syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194037 SCV001363275 likely benign not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: CACNA1C c.5098G>A (p.Gly1700Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 216132 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.5098G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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