ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.911T>C (p.Ile304Thr) (rs201756421)

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Total submissions: 8
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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 RCV000170766 SCV000050759 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000212338 SCV000223321 uncertain significance not specified 2017-04-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1C gene. The I304T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant has previously been observed independently or in conjunction with additional cardiogenetic variants in multiple other unrelated individuals referred for arrhythmia genetic testing at GeneDx. However, segregation data is uninformative. In addition, this variant has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000231571.1, SCV000259358.1, SCV000318927.1, SCV000280059.1; Landrum et al., 2016). The NHLBI Exome Sequencing Project and the Exome Aggregation Consortium (ExAC) report the I304T variant was observed in 10/8,588 alleles from individuals of European background and 58/66,110 alleles from individual of Non-Finnish European background, respectively. This substitution occurs at a position that is not conserved across species, and Threonine is the wild-type amino acid at this position in at least one species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the I304T variant results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000170766 SCV000231571 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing
Invitae RCV001082904 SCV000259358 likely benign Long QT syndrome 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247705 SCV000318927 likely benign Cardiovascular phenotype 2018-11-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000170766 SCV000697557 likely benign not provided 2016-08-09 criteria provided, single submitter clinical testing Variant summary: The CACNA1C c.911T>C (p.Ile304Thr) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 60/119182 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0008773 (58/66110). This frequency is about 88 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in one long QT patient with classification of polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Likely benign or VUS. Taken together, this variant is classified as Likely benign.
Ambry Genetics RCV000717413 SCV000848263 uncertain significance History of neurodevelopmental disorder 2017-09-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000212338 SCV000280059 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. Given the lack of case data and the rare occurrence in individuals not selected for Mendelian phenotypes, we consider this a variant of uncertain significance. The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts it to be tolerated. The isoleucine at codon 304 is not conserved across species. The variant was reported online in 30 of 60,304 individuals (including 29 of 36,923 European individuals, 1 of 4949 African-American individuals, and 1 of 5780 Latino Individuals) in the Exome Aggregation Consortium dataset ( (as of December 1st, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012).

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