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

gnomAD frequency: 0.00066  dbSNP: rs201756421

Total submissions: 10

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.
Eurofins Ntd Llc (ga)	RCV000170766	SCV000231571	uncertain significance	not provided	2018-09-11	criteria provided, single submitter	clinical testing
Invitae	RCV001082904	SCV000259358	likely benign	Long QT syndrome	2024-02-01	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
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224184	SCV003920649	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8; Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures	2021-03-30	criteria provided, single submitter	clinical testing	CACNA1C NM_000719.6 exon 6 p.Ile304Thr (c.911T>C): This variant has not been reported in the literature but is present in 0.1% (11/10290) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-2595423-T-C). This variant is present in ClinVar (Variation ID:190631). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000170766	SCV004129705	benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	CACNA1C: PP2, BS1, BS2
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 (http://exac.broadinstitute.org/) (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).