ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.4726+9G>A

gnomAD frequency: 0.00022  dbSNP: rs369267978
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000424344 SCV000512458 benign not specified 2015-03-31 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000540252 SCV000627552 benign Long QT syndrome 2024-01-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000424344 SCV001554643 benign not specified 2021-03-25 criteria provided, single submitter clinical testing Variant summary: CACNA1C c.4726+9G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 249784 control chromosomes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4726+9G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences RCV003950047 SCV004767408 likely benign CACNA1C-related disorder 2019-07-16 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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