Submissions for variant NM_000719.7(CACNA1C):c.985G>A (p.Gly329Ser)

dbSNP: rs786205744

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170767	SCV000223322	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing	p.Gly329Ser (GGC>AGC): c.985 G>A in exon 7 of the CACNA1C gene (NM_000719.6). The G329S variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The G329S variant was not observed in approximately 6,500 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 G329S variant 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. The G329 residue is conserved in mammals. In silico analysis predicts G329S is possibly damaging to the protein structure/function. However, no mutations in nearby residues have been reported in association with LQTS, indicating region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if G329S is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s).
Blueprint Genetics	RCV000208285	SCV000263795	uncertain significance	Sudden cardiac death	2015-02-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381542	SCV002693218	uncertain significance	Cardiovascular phenotype	2022-02-15	criteria provided, single submitter	clinical testing	The p.G329S variant (also known as c.985G>A), located in coding exon 7 of the CACNA1C gene, results from a G to A substitution at nucleotide position 985. The glycine at codon 329 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485064	SCV002786041	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-09-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517636	SCV003002440	uncertain significance	Long QT syndrome	2023-06-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 329 of the CACNA1C protein (p.Gly329Ser). This variant is present in population databases (rs786205744, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190632). 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. 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.
Revvity Omics, Revvity	RCV000170767	SCV003830330	uncertain significance	not provided	2022-03-23	criteria provided, single submitter	clinical testing