ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1114-304G>A (rs786205745)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170769 SCV000223324 pathogenic not provided 2014-01-28 criteria provided, single submitter clinical testing p.Gly406Arg (GGA>AGA): c.1216 G>A in exon 8 of the CACNA1C gene (NM_001167625.1). The G406R mutation 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. reported G406R as a de novo mutation in 11 unrelated individuals with Timothy syndrome and additionally in two siblings that inherited G406R as a result of germline mosaicism (Splawski I et al., 2004). 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 Gly406 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 mutation. The variant is found in ARRHYTHMIA panel(s).
GeneReviews RCV000192272 SCV000240237 pathogenic Timothy syndrome 2015-07-16 no assertion criteria provided literature only

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