ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1204G>A (p.Gly402Ser) (rs80315385)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000422493 SCV000515891 pathogenic not provided 2017-02-24 criteria provided, single submitter clinical testing The G402S variant in the primary transcript (exon 8) of the CACNA1C gene has been reportedpreviously in a patient with Timothy syndrome (Splawski et al., 2005), but the G402S variant in thealternate transcript has not been reported as pathogenic, nor as a benign polymorphism, toour knowledge. The G402S variant was not observed in approximately 6,000 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The G402S variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species. Functional studies haveshown that G402S results in nearly complete loss of voltage-dependent channel inactivation and likelyinduces calcium overload in multiple cell types (Depil et al., 2011). We interpret G402S as a pathogenic variant.
OMIM RCV000019200 SCV000039488 pathogenic Timothy syndrome 2005-06-07 no assertion criteria provided literature only
GeneReviews RCV000019200 SCV000040769 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 RCV000058284 SCV000089804 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported in the following publications (PMID:15863612;PMID:21685391).

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