ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2460+6G>A

gnomAD frequency: 0.00029  dbSNP: rs369246066
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000533865 SCV000627523 uncertain significance Long QT syndrome 2024-01-21 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369246066, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. 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: 456955). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
GeneDx RCV000994772 SCV001846019 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002470905 SCV002766876 uncertain significance Long qt syndrome 8 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with long QT syndrome 8 (MIM #618447), and Timothy syndrome (MIM#601005). Missense variants result in loss of channel inactivation and increased current (OMIM, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (44 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely benign, benign and as a VUS (LOVD, ClinVar). It was also observed in a SIDS cohort (PMID: 32145446). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000994772 SCV004562129 uncertain significance not provided 2023-10-10 criteria provided, single submitter clinical testing The CACNA1C c.2460+6G>A variant (rs369246066) is reported in the literature in a sudden infant death cohort, but without clear disease association (Liebrechts-Akkerman 2020). This variant is also reported in ClinVar (Variation ID: 456955), and is found in the general population with an overall allele frequency of 0.020% (39/191908 alleles) in the Genome Aggregation Database. This is an intronic variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant does not alter splicing. However, since this variant is located within the minimal splice region, the clinical significance of this variant is uncertain at this time. References: Liebrechts-Akkerman G et al. Explaining sudden infant death with cardiac arrhythmias: Complete exon sequencing of nine cardiac arrhythmia genes in Dutch SIDS cases highlights new and known DNA variants. Forensic Sci Int Genet. 2020 May;46:102266. PMID: 32145446.
Clinical Genetics, Academic Medical Center RCV001700403 SCV001918433 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001700403 SCV001930451 benign not specified no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000994772 SCV001958787 likely benign not provided no assertion criteria provided clinical testing

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