ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1216G>A (p.Gly406Arg) (rs79891110)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170771 SCV000223326 pathogenic not provided 2018-08-23 criteria provided, single submitter clinical testing The G406R variant in the CACNA1C gene has been reported previously in association with Timothy syndrome (Splawski I et al., 2004; Yarotskyy V et al., 2009). Splawski et al. (2004) reported G406R as a de novo variant in 11 unrelated individuals with Timothy syndrome and additionally in two siblings that inherited G406R as a result of germline mosaicism. In this same study, G406R was absent in 360 control alleles and expression of the CACNA1C gene was found in multiple tissue types that correlate to the organ systems affected in Timothy syndrome. Moreover, G406R 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 G406 residue is highly conserved across species and functional studies identified that G406R has a significant effect on calcium ion channel currents leading to action potential prolongation (Splawski I et al., 2004). G406R is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure.In summary, G406R in the CACNA1C gene is interpreted as a disease-causing variant.
Invitae RCV000199739 SCV000253858 pathogenic Long QT syndrome 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 406 of the CACNA1C protein (p.Gly406Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant is a recurrent de novo variant that has been reported in almost every individual diagnosed with Timothy syndrome (PMID: 15454078, 15863612, 23578275, 23580742, 26227324). It has also been shown to be inherited from a mosaic parent (PMID: 21910241, 23690510) as well as in a patient referred for long QT testing (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 17632). Experimental studies have shown that this variant reduces channel inactivation, which leads to aberrant intracellular calcium levels in multiple tissues (PMID: 15454078, 15863612, 18250309, 19074970, 26822303). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV000019199 SCV000805133 pathogenic Timothy syndrome 2018-04-04 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853375 SCV000996245 pathogenic CACNA1C-Related Disorders 2019-02-13 criteria provided, single submitter clinical testing This variant is located in the last amino acid of exon 8. This variant has been previously reported in multiple studies as a de novo heterozygous change in patients with Timothy Syndrome (PMID: 28371864, 23690510, 28211989, 15454078). A functional study showed this variant impairs voltage-dependent channel inactivation causing maintained inward calcium currents (PMID: 15454078). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1216G>A (p.Gly406Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1216G>A (p.Gly406Arg) variant is classified as pathogenic.
OMIM RCV000019199 SCV000039487 pathogenic Timothy syndrome 2011-03-10 no assertion criteria provided literature only
GeneReviews RCV000019199 SCV000040770 pathologic Timothy syndrome 2011-04-21 no assertion criteria provided curation Converted during submission to Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058285 SCV000089805 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported in the following publications (PMID:15454078;PMID:15863612;PMID:17224476;PMID:19074970;PMID:21878566).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000170771 SCV000924760 pathogenic not provided 2016-04-25 no assertion criteria provided provider interpretation

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