Submissions for variant NM_000719.7(CACNA1C):c.3331G>A (p.Val1111Ile)

gnomAD frequency: 0.00001  dbSNP: rs766023530

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472011	SCV000553006	uncertain significance	Long QT syndrome	2024-10-24	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 1111 of the CACNA1C protein (p.Val1111Ile). This variant is present in population databases (rs766023530, gnomAD 0.004%). 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: 411719). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714636	SCV000845350	uncertain significance	Timothy syndrome	2018-08-07	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853469	SCV000996380	uncertain significance	Sudden unexplained death	2017-10-04	criteria provided, single submitter	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
GeneDx	RCV001770357	SCV002002575	uncertain significance	not provided	2021-02-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#411719; Landrum et al., 2016)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252135	SCV002523144	uncertain significance	See cases	2021-05-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2
Ambry Genetics	RCV002323750	SCV002605575	uncertain significance	Cardiovascular phenotype	2021-02-03	criteria provided, single submitter	clinical testing	The p.V1111I variant (also known as c.3331G>A), located in coding exon 26 of the CACNA1C gene, results from a G to A substitution at nucleotide position 3331. The valine at codon 1111 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002481470	SCV002775077	uncertain significance	Timothy syndrome; Brugada syndrome 3; Long qt syndrome 8	2021-07-26	criteria provided, single submitter	clinical testing