ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2517C>A (p.Asn839Lys) (rs774002530)

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Total submissions: 2
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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).
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.

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