Submissions for variant NM_000719.7(CACNA1C):c.5671G>C (p.Ala1891Pro)

gnomAD frequency: 0.00007  dbSNP: rs542914369

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000305564	SCV000329184	uncertain significance	not provided	2016-01-07	criteria provided, single submitter	clinical testing	The A1891P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this variant was not observed in approximately 6,100 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 1000 Genomes Project reports A1891P was observed in approximately 0.1% of alleles from individuals of African background. The A1891P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating this region of the gene is not known to harbor pathogenic variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000538195	SCV000627572	uncertain significance	Long QT syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1891 of the CACNA1C protein (p.Ala1891Pro). This variant is present in population databases (rs542914369, gnomAD 0.03%). 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: 279723). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV002347983	SCV002653227	benign	Cardiovascular phenotype	2024-11-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002487172	SCV002785435	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-07-23	criteria provided, single submitter	clinical testing