Submissions for variant NM_000719.7(CACNA1C):c.4942G>A (p.Ala1648Thr)

gnomAD frequency: 0.00011  dbSNP: rs370432385

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724254	SCV000230504	uncertain significance	not provided	2014-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000178426	SCV000535948	uncertain significance	not specified	2017-01-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CACNA1C gene. The A1648T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A1648T was not observed with any significant frequency in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The A1648T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, where T1648 is the native residue in multiple species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae	RCV000468918	SCV000553017	likely benign	Long QT syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000522719	SCV000616613	uncertain significance	Timothy syndrome	2017-04-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724254	SCV001148532	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	CACNA1C: PP2
Ambry Genetics	RCV002336438	SCV002642731	uncertain significance	Cardiovascular phenotype	2019-03-07	criteria provided, single submitter	clinical testing	The p.A1648T variant (also known as c.4942G>A), located in coding exon 40 of the CACNA1C gene, results from a G to A substitution at nucleotide position 4942. The alanine at codon 1648 is replaced by threonine, an amino acid with similar properties. This variant was detected in an individual with short-coupled torsades de pointes and in her daughter with ventricular fibrillation and short-coupled premature ventricular beats, as well as in the proband's unaffected brother (Blancard M et al. Sci Rep, 2018 Oct;8:14619). The variant was also reported (as c.5086G>A p.A1696T) in a sudden unexplained death case with limited clinical details provided (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358). This amino acid position is well conserved in available vertebrate species; however, threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.