ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5339G>A (p.Arg1780His)

gnomAD frequency: 0.00001  dbSNP: rs756829999
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001216732 SCV001388544 likely benign Long QT syndrome 2024-01-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV002348723 SCV002647046 uncertain significance Cardiovascular phenotype 2019-03-18 criteria provided, single submitter clinical testing The p.R1780H variant (also known as c.5339G>A), located in coding exon 42 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5339. The arginine at codon 1780 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in a Japanese cohort in an individual with Brugada syndrome sign on ECG; however, the patient was asymptomatic and family history information was not available (Fukuyama M et al. Circ. J., 2013 Apr;77:1799-806). This amino acid position is poorly conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003414011 SCV004106318 uncertain significance CACNA1C-related disorder 2022-10-16 criteria provided, single submitter clinical testing The CACNA1C c.5339G>A variant is predicted to result in the amino acid substitution p.Arg1780His. This variant has been reported in the heterozygous state in a 57 year old asymptomatic male but diagnosed with Brugada syndrome (saddle-back type) pattern ECG at an annual health check-up (Case 4, Fukuyama et al. 2013. PubMed ID: 23575362). This variant has also been reported in a registry of variants associated with Brugada syndrome (Supplementary Table 1, Chen et al. 2019. PubMed ID: 30662450) and was reported as a variant of uncertain significance in a study of genetics associated with Brugada syndrome (Campuzano et al. 2019. PubMed ID: 30821013). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-2788857-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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