Submissions for variant NM_000719.7(CACNA1C):c.70C>T (p.Arg24Cys)

gnomAD frequency: 0.00002  dbSNP: rs773211348

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170813	SCV000223368	uncertain significance	not provided	2012-12-31	criteria provided, single submitter	clinical testing	p.Arg24Cys (CGC>TGC): c.70 C>T in exon 2 of the CACNA1C gene (NM_000719.6). The Arg24Cys variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg24Cys results in a non-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Cysteine at a position that is conserved across species. In silico analysis predicts Arg24Cys is possibly damaging to the protein structure/function. The NHLBI ESP Exome Variant Server reports Arg24Cys was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with LQTS. With the clinical and molecular information available at this time, we cannot definitively determine if Arg24Cys is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Invitae	RCV000473429	SCV000553018	uncertain significance	Long QT syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 24 of the CACNA1C protein (p.Arg24Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with long QT Syndrome (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 190675). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002362868	SCV002663114	uncertain significance	Cardiovascular phenotype	2021-09-20	criteria provided, single submitter	clinical testing	The p.R24C variant (also known as c.70C>T), located in coding exon 2 of the CACNA1C gene, results from a C to T substitution at nucleotide position 70. The arginine at codon 24 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a Brugada syndrome cohort; however, clinical details were limited (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.