Submissions for variant NM_000719.7(CACNA1C):c.5150C>G (p.Ala1717Gly)

gnomAD frequency: 0.00048  dbSNP: rs201492706

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000079296	SCV000050758	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000079296	SCV000111166	uncertain significance	not provided	2015-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000079296	SCV000223310	benign	not provided	2021-01-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22840528, 20817017)
Invitae	RCV001081791	SCV000259473	likely benign	Long QT syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212340	SCV000697549	likely benign	not specified	2019-03-18	criteria provided, single submitter	clinical testing	Variant summary: CACNA1C c.5150C>G (p.Ala1717Gly) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal 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 0.00076 in 272838 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 75.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.5150C>G has been reported in the literature in individuals affected with cardiac phenotypes (Burashnikov_2010, Crotti_2012, Forleo_2017, Kostareva_2016, Wemhoner_2015) however without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002336232	SCV002641062	likely benign	Cardiovascular phenotype	2018-06-28	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224137	SCV003919752	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 42 p.Ala1717Gly (c.5150C>G): This variant has not been reported in the literature but is present in 0.1% (41/34056) of Latino alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201492706). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign (Variation ID:93411). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as Likely Benign.
Dept of Medical Biology, Uskudar University	RCV001081791	SCV004022092	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, PP2
CeGaT Center for Human Genetics Tuebingen	RCV000079296	SCV004132349	benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	CACNA1C: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003952497	SCV004774412	likely benign	CACNA1C-related disorder	2024-02-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Blueprint Genetics	RCV000157124	SCV000206847	uncertain significance	Restrictive cardiomyopathy; Long QT syndrome	2014-06-24	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000288792	SCV000503535	likely benign	Brugada syndrome	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of Brugada syndrome.