ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2T>C (p.Met1Thr) (rs761378545)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170850 SCV000223405 uncertain significance not provided 2015-12-07 criteria provided, single submitter clinical testing p.Met1? (ATG>ACG): c.2 T>C in exon 1 of the CACNA1C gene (NM_000719.6). The c.2 T>C variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. This sequence variant alters the initiator Methionine residue and the resultant protein could be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. The c.2 T>C variant was not observed in approximately 6,000 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 variant is found in ARRHYTHMIA panel(s)."
Invitae RCV000528382 SCV000627528 uncertain significance Long QT syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the CACNA1C mRNA. The next initiator methionine is located in codon 8 of exon 1 and therefore this variant is expected to disrupt the first 7 amino acids of the protein. This variant is present in population databases (rs761378545, ExAC 0.01%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190710). In summary, this is a rare variant that disrupts the transcription start codon. However there is another initiator methionine that could potentially be used by the translation machinery. Further genetic and/or functional data is needed to classify this variant conclusively. For these reasons, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000765075 SCV000896280 uncertain significance Timothy syndrome; Brugada syndrome 3 2018-10-31 criteria provided, single submitter clinical testing

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