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
Labcorp Genetics (formerly Invitae), Labcorp	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212338	SCV000697557	likely benign	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: CACNA1C c.911T>C (p.Ile304Thr) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 248032 control chromosomes. The observed variant frequency is approximately 49.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05). c.911T>C has been reported in the literature in individuals affected with Long QT syndrome, arrythmia, and Brugada syndrome (Wemhoner_2015, VanLint_2019, Bora_2023, Novelli_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37901857, 34999275, 30847666, 25633834). ClinVar contains an entry for this variant (Variation ID: 190631). Based on the evidence outlined above, the variant was classified as likely benign.
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	2024-04-01	criteria provided, single submitter	clinical testing	CACNA1C: PP2, BS1, BS2
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV004813071	SCV005438454	likely benign	Timothy syndrome	2024-12-18	criteria provided, single submitter	clinical testing
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).