Submissions for variant NM_000719.7(CACNA1C):c.1255G>A (p.Gly419Arg)

dbSNP: rs786205776

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170836	SCV000223391	uncertain significance	not provided	2014-09-22	criteria provided, single submitter	clinical testing	p.Gly419Arg (GGA>AGA): c.1255 G>A in exon 9 of the CACNA1C gene (NM_000719.6). The G419R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G419R variant was not observed in approximately 6,400 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 G419R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with LQTS, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517641	SCV003353429	pathogenic	Long QT syndrome	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 419 of the CACNA1C protein (p.Gly419Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Timothy syndrome (PMID: 33191761). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 190697). 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 expected to disrupt CACNA1C protein function. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 33191761). For these reasons, this variant has been classified as Pathogenic.