Submissions for variant NM_000719.7(CACNA1C):c.3679G>A (p.Val1227Ile)

gnomAD frequency: 0.00006  dbSNP: rs373124557

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725545	SCV000337633	uncertain significance	not provided	2015-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463570	SCV000553002	uncertain significance	Long QT syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1227 of the CACNA1C protein (p.Val1227Ile). This variant is present in population databases (rs373124557, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 234984). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000618584	SCV000737427	benign	Cardiovascular phenotype	2023-12-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Fulgent Genetics, Fulgent Genetics	RCV002478822	SCV000894756	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000725545	SCV001805791	uncertain significance	not provided	2020-05-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725545	SCV004563479	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	The CACNA1C c.3679G>A; p.Val1227Ile variant (rs373124557), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 234984). This variant is found in the general population with an overall allele frequency of 0.0035% (10/282176 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.283). Due to limited information, the clinical significance of this variant is uncertain at this time.
Breakthrough Genomics, Breakthrough Genomics	RCV000725545	SCV005191608	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genomics Laboratory, Stanford Medicine	RCV005251101	SCV005902360	uncertain significance	Timothy syndrome; QT prolongation and arrhythmias in the absence of other syndromic features; arrhythmogenic disorders; short QT interval with or without a Brugada syndrome ECG pattern	2023-06-07	criteria provided, single submitter	clinical testing	The p.Val1227Ile variant in the CACNA1C gene has not been previously reported in association with disease. This variant has also been identified in 8/129006 European (non-Finnish) chromosomes (10/282176 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 234984). The CACNA1C gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that this variant is neither deleterious nor benign; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Val1227Ile variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP2]
Clinical Genomics Laboratory, Stanford Medicine	RCV005252825	SCV005908033	uncertain significance	Timothy syndrome; arrhythmogenic disorders	2023-06-07	criteria provided, single submitter	clinical testing	The p.Val1227Ile variant in the CACNA1C gene has not been previously reported in association with disease. This variant has also been identified in 8/129006 European (non-Finnish) chromosomes (10/282176 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 234984). The CACNA1C gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that this variant is neither deleterious nor benign; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Val1227Ile variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; PP2]
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223923	SCV000280057	uncertain significance	not specified	2012-03-18	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. Based on the data reviewed we consider this a variant of uncertain significance. This is a novel variant. It is not reported in dbSNP as a benign polymorphism nor is it reported in published literature in association with disease. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Leucine. Valine is not conserved at this position across species and there are no reported disease associated variants at nearby codons (Google, Gene Connection for the Heart Database, Mutadatabase). In silico analysis (PolyPhen) predicts the amino acid change to be benign. The reporting lab did not find this variant in 600 presumably healthy controls consisting of both Caucasian and African American ancestry.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415626	SCV000493714	uncertain significance	Short QT Syndrome 4	2015-07-24	no assertion criteria provided	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000656705	SCV000747830	uncertain significance	Timothy syndrome	2017-12-01	no assertion criteria provided	clinical testing	The observed variant c.3679G>A (p.V1227I) is not reported in 1000 Genomes and has minor allele frequency of 0.00002479 in ExAC database. The in silico prediction of the variant is benign by MutationTaster2 and tolerated by SIFT.