Submissions for variant NM_000719.7(CACNA1C):c.2854-4G>A

gnomAD frequency: 0.00007  dbSNP: rs113929946

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589613	SCV000697546	benign	not provided	2017-01-16	criteria provided, single submitter	clinical testing	Variant summary: The CACNA1C c.2854-4G>A variant involves the alteration of a non-conserved intronic nucleotide, which 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 7/120806 (1/17259), predominantly in the European (Non-Finnish) cohort, 6/66684 (1/11113), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CACNA1C variant of 1/100000. Therefore, suggesting this variant is likely a benign polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Therefore, due to the frequency observed in the ExAC control population, the variant of interest has been classified as Benign.
Invitae	RCV001084807	SCV000752893	likely benign	Long QT syndrome	2024-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000589613	SCV001945164	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002438525	SCV002749895	likely benign	Cardiovascular phenotype	2018-04-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV003224341	SCV003920650	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 22 c.2854-4G>A: This variant has not been reported in the literature and is present in 0.01% (4/24432) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-2711016-G-A). This variant is present in ClinVar (Variation ID:496072). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003905508	SCV004721789	likely benign	CACNA1C-related disorder	2022-02-23	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).