Submissions for variant NM_000719.7(CACNA1C):c.6329dup (p.Glu2111fs)

dbSNP: rs771708175

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454638	SCV000538551	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF not a known disease mechanism for CACNA1C ; ExAC: 2/57170 European chromosomes
Invitae	RCV000477263	SCV000553027	uncertain significance	Long QT syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2111Argfs*15) in the CACNA1C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the CACNA1C protein. This variant is present in population databases (rs771708175, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190695). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223803	SCV002503012	uncertain significance	not provided	2021-11-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485068	SCV002775541	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-10-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165344	SCV003855115	uncertain significance	Cardiovascular phenotype	2023-02-14	criteria provided, single submitter	clinical testing	The c.6329dupG variant, located in coding exon 47 of the CACNA1C gene, results from a duplication of G at nucleotide position 6329, causing a translational frameshift with a predicted alternate stop codon (p.E2111Rfs*15). This alteration occurs at the 3' terminus of theCACNA1C gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 1% of the protein. The exact functional effect of this alteration is unknown. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association with CACNA1C-related Timothy syndrome or long QT syndrome is unlikely.