ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.3969C>T (p.Ile1323=) (rs201345843)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723717 SCV000111160 uncertain significance not provided 2013-10-16 criteria provided, single submitter clinical testing
GeneDx RCV000723717 SCV000329182 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing The c.3969 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3969 C>T variant was not observed with any significant frequency in approximately 6,500 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 c.3969 C>T variant results in a synonymous amino acid substitution, I1323I, and in silico splice prediction programs are unable to predict whether this nucleotide substitution has an impact on normal gene splicing. Additionally, the majority of variants in the CACNA1C gene are missense changes (Stenson et al., 2014), indicating haploinsufficiency of CACNA1C may not be sufficient to cause disease. Nevertheless, this substitution occurs at a position that is conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001083964 SCV000627542 likely benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781193 SCV000919076 benign not specified 2017-11-06 criteria provided, single submitter clinical testing Variant summary: The CACNA1C c.3969C>T (p.Ile1323Ile) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 15/277196 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000118 (15/126706). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant has been reported in the literature, without strong evidence for causality. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as benign.

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