ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.5918G>A (p.Arg1973Gln) (rs112414325)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000079305 SCV000050757 likely benign not provided 2013-06-24 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000223757 SCV000111175 benign not specified 2016-06-21 criteria provided, single submitter clinical testing
Invitae RCV000079305 SCV000285600 benign not provided 2019-02-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000241853 SCV000319009 benign Cardiovascular phenotype 2016-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000331795 SCV000377925 likely benign Brugada syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000386344 SCV000377926 likely benign Timothy syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000223757 SCV000512465 benign not specified 2016-10-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000079305 SCV000697556 likely benign not provided 2016-01-25 criteria provided, single submitter clinical testing Variant summary: CACNA1C c.5918G>A affects a conserved nucleotide, resulting in amino acid change from Arg to Gln. 3/4 in-silico tools predict this variant to be benign. This variant is found in 433/121010 control chromosomes including the large and broad populations from ExAC at a frequency of 0.0035782, which is about 358 times greater than the maximal expected frequency of a pathogenic allele (0.00001) in this gene, suggesting this variant is benign. Five homozygotes were reported in ExAC. This variant has been reported in multiple LQTS and BrS patients without strong evidence for causality (eg. co-segregation studies). Clinical diagnostic labs have classified this variant as a VUS or likely benign before the large and diverse ExAC control cohorts were available. Taken together, this variant was classified as likely benign.
Ambry Genetics RCV000716980 SCV000847825 benign History of neurodevelopmental disorder 2016-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Blueprint Genetics RCV000157127 SCV000206850 likely benign short QT syndrome 2014-10-14 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223757 SCV000280058 uncertain significance not specified 2014-12-02 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 is novel. Pathogenic variants in CACNA1C are associated with Timothy syndrome and Brugada syndrome. This is a semi-conservative amino acid change with a hydrophilic basic polar Arginine replaced with a hydrophilic polar Glutamine. The variant is found in a highly conserved region of the CACNA1C gene. The reporting lab observed the variant in 2 out of 353 presumably healthy individuals of mixed ethnic background. Based on these data it is currently unclear whether this variant can cause disease, however given the presence in controls for a variant in a gene thus far only associated with quite rare diseases, it seems most likely that this variant does not cause rare Mendelian disease such as long QT syndrome.

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