Submissions for variant NM_000719.7(CACNA1C):c.2517C>A (p.Asn839Lys)

gnomAD frequency: 0.00001  dbSNP: rs774002530

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766674	SCV000223344	uncertain significance	not provided	2012-02-28	criteria provided, single submitter	clinical testing	The Asn839Lys variant in the CACNA1C gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Asn839Lys results in a semi-conservative amino acid substitution of an uncharged, polar Asparagine residue with a positively charged Lysine residue at a position that is conserved in mammalian species. Also, the NHLBI ESP Exome Variant Server reports Asn839Lys was not observed in approximately 5,000 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 indicating this region of the protein may be tolerant of change. Furthermore, multiple in silico analyses yield conflicting predictions regarding the effect of Asn839Lys on the protein structure/function. In summary, with the clinical and molecular information available at this time, we cannot unequivocally determine if the Asn839Lys variant is a disease-causing mutation or a rare benign variant. The variant is found in BRUGADA panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852042	SCV002172328	likely benign	Long QT syndrome	2023-12-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426809	SCV002744367	likely benign	Cardiovascular phenotype	2022-10-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000170789	SCV000280056	uncertain significance	not specified		no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This variant appears to be completely novel. As of March 15, 2012, no variation at codon 839 of CACNA1C has been reported in the literature (according to searches of PubMed and Google), either in association with Brugada syndrome or as a benign polymorphism. No disease-causing variants at nearby codons of CACNA1C (within 10 amino acids to either side) have been associated with disease, suggesting this region of the protein may be tolerant of change. However, deletion of residue 850 has been associated with early repolarization (inherited arrhythmias database: Molecular Cardiology Laboratories of IRCCS Fondazione Salvatore Maugeri). p.Asn839Lys is a nonconservative amino acid change from a polar, uncharged Asparagine to a basic, positively-charge Lysine. The Asparagine at codon 839 is highly conserved across 33 vertebrate species examined; it is a different amino acid (Arginine) only in Alpaca. Surrounding residues are also highly conserved, although to a lesser degree. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be benign. In total the variant has not been seen in ~4900 individuals from publicly available population datasets. There is no variation at codon 839 listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~3300 Caucasian and ~1600 African American individuals. There is also no variation at this codon listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of March 15, 2012.