ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys) (rs786205748)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170780 SCV000223335 pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing The R518C variant has not been reported as a disease causing variant or as a benign polymorphism, to our knowledge. R518C is a non-conservative amino acid change of a positively charged Arginine with a neutral, polar Cysteine residue. In addition, R518 is located in a region of the protein conserved through evolution. The R518C 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. Nevertheless, no disease-causing variants have been reported in the surrounding region of the protein, indicating this region may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000232889 SCV000285587 pathogenic Long QT syndrome 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 518 of the CACNA1C protein (p.Arg518Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). However, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. ClinVar contains an entry for this variant (Variation ID: 190642). This variant has been reported to segregate with the disease in three families affected with long QT syndrome (LQTS), hypertrophic cardiomyopathy (HCM) and septal defects (CHD) (PMID: 26253506, Invitae). Experimental studies have shown that this variant decreases the voltage-dependent inactivation of the channel (PMID: 26253506). In summary, this variant has been found to segregate with the disease in three affected families and leads to a gain of function of the channel. For these reasons, this variant has been classified as Pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000170780 SCV000924764 likely pathogenic not provided 2016-04-14 no assertion criteria provided provider interpretation

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